Download Assessment Report - Medical Services Advisory Committee

Review of Interim
Funded Service:
Brachytherapy for
the treatment of
prostate cancer
December 2010
MSAC application 1089.1
Assessment report
© Commonwealth of Australia 2011
Review of Interim Funded Service: Brachytherapy for the Treatment of Prostate Cancer
ISBN (print) 978-1-74241-359-4
ISBN (online) 978-1-74241-360-0
ISSN (print) 1443-7120
ISSN (online) 1443-7139
First printed March 2011
Paper-based publications
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Electronic copies of the report can be obtained from the Medical Service Advisory Committee’s
Internet site at http://www.msac.gov.au/
Printed copies of the report can be obtained from:
The Secretary
Medical Services Advisory Committee
Department of Health and Ageing
Mail Drop 853
GPO Box 9848
Canberra ACT 2601
Enquiries about the content of the report should be directed to the above address.
The Medical Services Advisory Committee (MSAC) is an independent committee which has been
established to provide advice to the Minister for Health and Ageing on the strength of evidence
available on new and existing medical technologies and procedures in terms of their safety,
effectiveness and cost-effectiveness. This advice will help to inform government decisions about
which medical services should attract funding under Medicare.
The MSAC’s recommendations do not necessarily reflect the views of all individuals who
participated in the MSAC evaluation.
This report was prepared by Mr David Tamblyn, Mr Ben Ellery and Ms Tracy Merlin from
Adelaide Health Technology Assessment (AHTA), Discipline of Public Health, the University of
Adelaide, with the assistance of an Advisory Panel of experts. The report was commissioned by
the Department of Health and Ageing on behalf of the Medical Services Advisory Committee
(MSAC). It was edited by Ms Jo Mason, Mason Edit, South Australia.
This report should be referenced as follows:
Tamblyn D, Ellery B, Merlin T (2011). Brachytherapy for the treatment of prostate cancer. MSAC
Application 1089.1, Review of Interim Funded Service. Canberra, ACT: Commonwealth of
Australia.
Publications Number: D0137
Contents
Executive summary............................................................................................... viii
Medical Services Advisory Committee—role and approach.................................. viii
Assessment of low-dose-rate brachytherapy ............................................................ viii
Introduction ..............................................................................................................1
Rationale for assessment................................................................................................. 1
Background .............................................................................................................. 2
Previous MSAC assessments ......................................................................................... 2
Brachytherapy................................................................................................................... 3
Clinical need / burden of disease ................................................................................ 10
Existing procedures ....................................................................................................... 14
Marketing status of the technology ............................................................................. 16
Current reimbursement arrangements........................................................................ 17
Approach to assessment ......................................................................................... 18
Objective ......................................................................................................................... 18
Clinical pathway ............................................................................................................. 18
Comparator..................................................................................................................... 22
Research questions ........................................................................................................ 22
Expert advice.................................................................................................................. 23
Review of literature ....................................................................................................... 23
Appraisal of the evidence ............................................................................................. 27
Assessment of the body of evidence .......................................................................... 30
Results of assessment ............................................................................................. 31
Is it safe?.......................................................................................................................... 31
Is it effective? ................................................................................................................. 54
What are the economic considerations? ..................................................................... 61
Discussion .............................................................................................................. 82
Is it safe?.......................................................................................................................... 82
Is it effective? ................................................................................................................. 91
What are the economic considerations? ..................................................................... 96
Other relevant considerations...................................................................................... 99
Conclusions ........................................................................................................... 106
Safety ............................................................................................................................. 106
Effectiveness ................................................................................................................ 107
Economic considerations ........................................................................................... 108
Appendix A MSAC terms of reference and membership ....................................111
Appendix B
Advisory Panel and Evaluators ..................................................... 113
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page iii of 261
Advisory Panel – Application 1089.1 – Brachytherapy for the treatment
of prostate cancer ........................................................................................................ 113
Evaluation Sub-committee input............................................................................... 113
Evaluators ..................................................................................................................... 113
Appendix C Search strategies............................................................................. 114
Appendix D Data tables for urinary side effects ................................................ 118
Appendix E Data tables for bowel side effects .................................................. 135
Appendix F Data tables for sexual dysfunction side effects .............................. 148
Appendix G Data tables for health-related quality of life .................................. 159
Appendix H Data tables for primary and secondary effectiveness.................... 172
Appendix I Data tables for economic considerations........................................ 177
Appendix J Studies included in the review ........................................................ 182
Profiles of included studies on safety and effectiveness ........................................ 182
Study profiles of included case series ....................................................................... 206
Appendix K Other eligible case series ............................................................... 211
Appendix L Excluded studies ............................................................................ 216
Appendix M
Unit costs for treating localised prostate cancer..........................236
Glossary and abbreviations ...................................................................................245
References .............................................................................................................248
Page iv of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Tables
Table 1
Indications for low-dose-rate brachytherapy according to
international guidelines ............................................................................................ 6
Table 2
UICCa tumour–nodes–metastasis staging system for prostate cancer.............. 7
Table 3
Item numbers and utilisation for prostate brachytherapy and open
prostatectomy .......................................................................................................... 13
Table 4
Medicare Benefits Scheme item numbers and reimbursement for lowdose-rate brachytherapy for localised prostate cancer....................................... 17
Table 5
Bibliographic databases .......................................................................................... 23
Table 6
Search strategy ......................................................................................................... 24
Table 7
Evidence dimensions.............................................................................................. 28
Table 8
Designations of levels of evidence according to intervention research
question .................................................................................................................... 28
Table 9
Quality assessment of studies with Downs and Black ...................................... 29
Table 10
Body of evidence assessment matrix ................................................................... 30
Table 11
Primary effectiveness outcomes comparing LDRBT, RP and EBRT ............ 58
Table 12
Secondary effectiveness outcomes comparing LDRBT, RP and
EBRT........................................................................................................................ 59
Table 13
Total and incremental quality adjusted life years, total and incremental
cost, and incremental cost-effectiveness ratio (cost/QALY) of active
surveillance, low-dose-rate brachytherapy and intensity modulated
radiotherapy compared with radical prostatectomy for the treatment
of localised prostate cancer ................................................................................... 64
Table 14
Services associated with low-dose-rate 125I brachytherapy, external
beam radiotherapy, radical prostatectomy and active surveillance for
localised prostate cancer ........................................................................................ 68
Table 15
Costs associated with the treatment of localised prostate cancer .................... 71
Table 16
Costs of treating localised prostate cancer in the private sector—by
Gleason score .......................................................................................................... 72
Table 17
Cost of follow-up and cumulative costs of treatment for localised
prostate cancer in the private sector—for patients with Gleason score
≤ 6a ............................................................................................................................ 72
Table 18
Costs and source of funding for the treatment of one man with
localised prostate cancer in a private setting with 10 years follow-up ............ 73
Table 19
Costs and source of funding for the treatment of one man with
localised prostate cancer in a public setting with 10 years follow-up.............. 73
Table 20
Scenario 1: Total costs borne by MBS, other governmental bodies,
and patient or private insurance over a 10-year period based on onethird of all men electing each treatment .............................................................. 75
Table 21
Costs associated with active surveillance for localised prostate cancer .......... 79
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page v of 261
Table 22
Scenario 2: Total discounted costs borne by MBS, Australian
healthcare system, and patient or private insurance over a 10-year
period for treating 5,000 men, with 20% of Gleason ≤ 6 men opting
for active surveillance1 ............................................................................................ 79
Table 23
Total cost to the Australian healthcare system of treating 5,000 men
with localised prostate cancer for different rates of active surveillance
(AS) and different likelihoods of opting out of AS ........................................... 80
Table 24
Assessment of body of evidence for the safety of low-dose-rate
brachytherapy compared with external beam radiotherapy for the
treatment of localised prostate cancera ................................................................ 86
Table 25
Assessment of body of evidence for the safety of low-dose-rate
brachytherapy compared with radical prostatectomy for the treatment
of localised prostate cancera .................................................................................. 87
Table 26
Assessment of body of evidence for the safety of low-dose-rate
brachytherapy compared with active surveillance for the treatment of
localised prostate cancera ....................................................................................... 88
Table 27
Assessment of body of evidence for the effectiveness of low-doserate brachytherapy compared with external beam radiotherapy and
radical prostatectomy for the treatment of localised prostate cancera,b .......... 95
Table 28
Additional sources of literature........................................................................... 114
Table 29
Consumer and professional websites for additional information.................. 115
Table 30
Websites of health technology assessment agencies........................................ 116
Table 31
Urinary side effects resulting from low-dose-rate brachytherapy,
radical prostatectomy, external beam radiotherapy and active
surveillance for the treatment of localised prostate cancer............................. 118
Table 32
Bowel side effects resulting from low-dose-rate brachytherapy, radical
prostatectomy, external beam radiotherapy and active surveillance for
the treatment of localised prostate cancer......................................................... 135
Table 33
Sexual dysfunction resulting from low-dose-rate brachytherapy,
radical prostatectomy, external beam radiotherapy and active
surveillance for the treatment of localised prostate cancer............................. 148
Table 34
Effects on health-related quality of life resulting from low-dose-rate
brachytherapy, radical prostatectomy, external beam radiotherapy and
active surveillance for the treatment of localised prostate cancer ................. 159
Table 35
Studies comparing primary or secondary effectiveness outcomes for
low-dose-rate brachytherapy, radical prostatectomy, external beam
radiotherapy and active surveillance for the treatment of localised
prostate cancer ...................................................................................................... 172
Table 36
Economic considerations of low-dose-rate brachytherapy compared
with radical prostatectomy, external beam radiotherapy and active
surveillance for the treatment of localised prostate cancer............................. 177
Table 37
Unit costs of services and medications relating to low-dose-rate 125I
brachytherapy for localised prostate cancer over a 12-month period........... 236
Page vi of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 38
Unit costs of services and medications relating to radical external beam
radiotherapy for localised prostate cancer over a 12-month
period...................................................................................................................... 240
Table 39
Unit costs of services and medications relating to radical
prostatectomy for localised prostate cancer over a 12-month period........... 242
Table 40
Unit costs of services and medications relating to active surveillance
for localised prostate cancer over a 12-month period..................................... 244
Box 1
Inclusion criteria for studies assessing the safety of low-dose-rate
brachytherapy for the treatment of localised prostate cancer .......................... 32
Box 2
Inclusion criteria for studies assessing the effectiveness of low-doserate brachytherapy for the treatment of localised prostate cancer .................. 55
Box 3
Inclusion criteria for studies assessing the cost-effectiveness of lowdose-rate brachytherapy for the treatment of localised prostate cancer ......... 62
Boxes
Figures
Figure 1
Clinical pathway for men diagnosed with localised prostate cancer
with Gleason score = 6 .......................................................................................... 19
Figure 2
Clinical pathway for men diagnosed with localised prostate cancer
with primary Gleason grade = 3 and secondary Gleason grade = 4
(Gleason score = 7) ................................................................................................ 20
Figure 3
Clinical pathway for men diagnosed with localised prostate cancer
with primary Gleason grade = 4 and secondary Gleason grade = 3
(Gleason score = 7) ................................................................................................ 21
Figure 4
PRISMA flowchart outlining the process of study selection ........................... 26
Figure 5
Actual and projected numbers of low-dose-rate brachytherapy
procedures (item number 15338) by financial year ............................................ 66
Figure 6
Transition to and from active surveillance to treatment over 10 years........... 78
Figure 7
Patient journey for a man diagnosed with localised prostate cancer............. 103
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page vii of 261
Executive summary
Medical Services Advisory Committee—role and approach
The Medical Services Advisory Committee (MSAC) was established by the Australian
Government to strengthen the role of evidence in health financing decisions in Australia.
The MSAC advises the Minister for Health and Ageing on the evidence relating to the
safety, effectiveness and cost-effectiveness of new and existing medical technologies and
procedures, and under what circumstances public funding should be supported.
Assessment of low-dose-rate brachytherapy
Purpose of application
The review of the interim Medicare Benefits Schedule (MBS) listing of low-dose-rate
(LDR) brachytherapy (BT) for men with localised prostate cancer was requested by the
Australian Department of Health and Ageing. This assessment of the safety, effectiveness
and cost-effectiveness of LDRBT follows Application 1029 (Medical Services Advisory
Committee 2000), which resulted in the interim listing of LDRBT on the MBS, and
Application 1089 (Medical Services Advisory Committee 2005), which resulted in the
continued interim listing on the MBS.
LDRBT, or permanent seed BT, is the implantation of radioisotopes (iodine-125 or
palladium-103) directly into the prostate gland for the treatment of localised prostate
cancer. The procedure is performed under transrectal ultrasound guidance and may
require an overnight stay in hospital. Before implantation—either 1 week or so before, or
sometimes during, the procedure—the distribution of radioactive seeds is planned to
ensure adequate distribution of radiation throughout the prostate. The distribution of the
seeds is then verified at another visit (often 1 month later) using computerised
tomography to identify any seed migration. The procedure requires the expertise of a
radiation oncologist, urologist, radiation therapist and radiation physicist.
While LDRBT may be delivered in combination with external beam radiotherapy
(EBRT), this report analysed only LDRBT used alone. In addition, the review has only
considered evidence regarding LDRBT delivered using iodine-125 radioactive seeds, as
other radioisotopes used in the procedure are not available in Australia.
LDRBT is currently listed on the MBS for men with localised, low- to intermediate-risk
prostate cancer. Specifically, to qualify for reimbursement, men must have a prostate
specific antigen (PSA) level of ≤ 10 ng/mL, a tumour with a clinical stage of T1 or T2
(confined to the prostate) and a Gleason score of ≤ 7.
A rigorous assessment of evidence is the basis of decision making when public funding is
sought. A team from Adelaide Health Technology Assessment in the Discipline of Public
Health, School of Population Health and Clinical Practice within the University of
Adelaide, was commissioned by the Department of Health and Ageing to conduct a
systematic review of the literature on the use of LDR 125I BT for the treatment of
localised prostate cancer. An advisory panel with expertise in this area provided advice to
Page viii of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
the MSAC to assist with this evaluation of the safety, effectiveness and cost-effectiveness
of LDRBT for the treatment of localised prostate cancer.
Current arrangements for public reimbursement
LDRBT currently receives interim funding through the MBS, which provides
reimbursement for professional fees and services associated with the procedure. The
substantial cost of the BT seeds is covered by private health insurance but is not
universally funded by state/territory governments for patients accessing the technology
through the public healthcare system.
Item 15338
PROSTATE, radioactive seed implantation of, radiation oncology component, using transrectal ultrasound guidance, for
localised prostatic malignancy at clinical stages T1 (clinically inapparent tumour not palpable or visible by imaging) or T2
(tumour confined within prostate), with a Gleason score of less than or equal to 7 and a prostate specific antigen (PSA) of
less than or equal to 10ng/ml at the time of diagnosis. The procedure must be performed at an approved site in association
with a urologist.
Fee: $884.25 Benefit: 75% = $663.20 85% = $815.15
Item 37220
PROSTATE, radioactive seed implantation of, urological component, using transrectal ultrasound guidance, for localised
prostatic malignancy at clinical stages T1 (clinically inapparent tumour not palpable or visible by imaging) or T2 (tumour
confined within prostate), with a Gleason score of less than or equal to 7 and a prostate specific antigen (PSA) of less than
or equal to 10ng/ml at the time of diagnosis. The procedure must be performed by a urologist at an approved site in
association with a radiation oncologist, and be associated with a service to which item 55603 applies.
Fee: $986.90 Benefit: 75% = $740.20
Item 15539
BRACHYTHERAPY PLANNING, computerised radiation dosimetry for 125I seed implantation of localised prostate cancer,
in association with item 15338
Fee: $592.90 Benefit: 75% = $444.70 85% = $523.80
Source: http://www9.health.gov.au/mbs/search.cfm (MBS Online - accessed 29 October 2010)
Background
LDRBT has been considered by the MSAC on two previous occasions. In 2000 the
MSAC recommended the interim funding of LDRBT for the treatment of men with
localised prostate cancer with a Gleason score ≤ 6 and a PSA ≤ 10 ng/mL. This
recommendation was accepted by the Minister for Health and Aged Care on 9 February
2001. In 2005 the MSAC recommended the continuation of interim funding of LDRBT
for the treatment of localised prostate cancer within the same population. This
recommendation was accepted by the Minister for Health and Ageing on 28 November
2005.
In 2006 an application was made by the Australian and New Zealand Association of
Urological Surgeons (ANZAUS) to have the eligibility criteria for MBS reimbursement
expanded to include men with Gleason scores of 7. A critique of the studies submitted by
ANZAUS to support this revision was undertaken by the National Health and Medical
Research Council (NHMRC) Clinical Trials Centre. The studies were assessed as being
supportive of extending the Gleason score cut-off for MBS reimbursement from 6 to 7;
however, evidence was not sought or appraised systematically. This recommendation was
accepted by the Minister for Health and Ageing, and the MBS reimbursement criteria was
altered in the July 2007 supplement (Medicare Australia 2007).
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page ix of 261
Clinical need
Prostate cancer is the most commonly diagnosed cancer in Australian men (excluding
non-melanocytic skin cancer). In 2006, 17,444 new cases of prostate cancer were
diagnosed in Australia and 2,952 deaths were attributed to the disease. Age-standardised
incidence rates have been increasing since 2000 following a peak of 184.3 per 100,000
men (age standardised to the 2001 Standard Australian Population) in 1994, which was
largely attributed to the introduction of PSA testing.
Currently, almost one in seven men will be diagnosed with prostate cancer before the age
of 75 years and more than one in five men before the age of 85 years. Due to greater
awareness of the disease and the introduction of PSA testing, many men will be identified
with localised prostate cancer, and will potentially be amenable to curative treatments.
Prostate cancer is a heterogeneous disease ranging from indolent and unlikely to pose a
threat to a man in his lifetime, to aggressive and life threatening. There are several known
prognostic markers—such as PSA level (or rate of change), clinical stage and Gleason
score—which may help identify more aggressive cancers. However, despite considerable
effort in the area of risk assessment, substantial uncertainty still remains regarding the
determination of which cancers require intervention and the most appropriate timing of
the intervention.
Perhaps as a result of earlier detection of, or innovations in treatment for, prostate
cancer, the age standardised mortality rate is steadily falling, from 43.7 per 100,000 in
1993 to 31.0 per 100,000 in 2007. Despite a decline in mortality rates, prostate cancer
remains an important disease, responsible for more deaths than any other cancer in men
with the exception of lung cancer.
It is estimated that 5,000 men will be eligible for LDRBT in 2010 and 1,400 procedures
will be performed. This represents an increase of about 400 procedures from the most
recent data available in the 2007–08 financial year. The number of LDRBT procedures
will be contingent upon access to a radiotherapy centre offering the procedure, as well as
the community preference for LDRBT in comparison to competing procedures such as
external beam radiotherapy, radical prostatectomy and active surveillance.
Comparators
Three comparators were identified for this review with respect to treatment for localised
prostate cancer—external beam radiotherapy (EBRT), radical prostatectomy (RP) and
active surveillance (AS).
Radical prostatectomy
RP is the surgical removal of the entire prostate gland, which can be performed either as
an open procedure or laparoscopically. More recently, robot-assisted laparoscopic
techniques have been developed and are available in certain centres around Australia.
RP is an invasive procedure requiring anaesthetic and is not offered to men with
significant comorbidities due to the risk imposed by the surgery. It is not often offered to
men over the age of 75 years.
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External beam radiotherapy
EBRT is the irradiation of the prostate gland, typically with high-energy photons from a
linear accelerator. EBRT is delivered as an outpatient procedure over a period of 6–
8 weeks. The duration of each treatment session is about 10 minutes, and most of the
time is required for preparation.
EBRT is a relatively non-invasive procedure, although modern techniques may require
the implantation of tiny markers (usually three) in the prostate to enable accurate
targeting of the radiotherapy.
Active surveillance
AS is the close monitoring of men with prostate cancer, who would otherwise be eligible
for curative treatment, for signs of progression or advancing disease. The aim of AS is to
delay treatment, perhaps indefinitely, or until it is clear that the patient has a type of
prostate cancer that is not indolent or insignificant.
It is not clear how commonly AS is practised in Australia; however, its use is growing
overseas.
Safety
A total of 14, 16, 11 and 11 comparative studies (level II to III-3 evidence) reported on
the urinary side effects, bowel side effects, sexual dysfunction and health-related quality
of life of patients receiving low-dose-rate brachytherapy (LDRBT) compared with
external beam radiotherapy (EBRT), radical prostatectomy (RP) or active surveillance
(AS).
Key results
Irritative or obstructive urinary symptoms
The most common side effect associated with the treatment of prostate cancer with
LDRBT is a transient increase in irritative (painful urination, urinary frequency, urgency)
and obstructive (difficulty passing urine, dribbling and urinary retention) symptoms. In all
included studies comparing LDRBT and RP, urinary irritation was greater following
LDRBT than RP, with four studies showing an enduring difference between the
treatments beyond 1 year. As reported by the only randomised controlled trial, there was
no difference in irritative or obstructive symptoms at 5 years compared with baseline
symptoms in men receiving either LDRBT or RP.
Compared with EBRT, two studies reported worse urinary irritation following LDRBT
and two reported no difference. Only one study comparing EBRT with LDRBT
controlled for baseline urinary function and this found no difference in irritative or
obstructive symptoms between the groups.
No study compared irritative or obstructive symptoms following LDRBT with AS.
Urinary incontinence
Urinary incontinence was less common following LDRBT than following RP.
Incontinence (or the need to wear incontinence pads) was consistently higher in the RP
group beyond 3 years following treatment. Incontinence was worse immediately
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page xi of 261
following treatment, and was reported by 68% of men receiving RP and 17% of men
receiving LDRBT. By 3 years following treatment, reported differences between the
treatment groups were modest, with 12% of men treated with RP and 7% treated with
LDRBT continuing to experience incontinence.
Four studies comparing urinary incontinence following LDRBT and EBRT reported no
difference; however, one study reported an increase in usage of pads among men treated
with LDRBT at 1 month. By 3 years, incontinence was reported by 2.7% of men treated
with EBRT.
Only one study reported on incontinence rates among men managed with AS, with 3.4%
of men requiring pads at 3 years. However, a proportion of men recorded as receiving AS
at baseline had opted for active treatment, and the rate of incontinence is likely to be
contingent upon the effect of the chosen treatment.
Urethral stricture
There was substantial heterogeneity of urethral stricture rates among studies involving
LDRBT. Urethral stricture was reported in 0.15–14% of men receiving LDRBT, 6.5%
receiving RP and 2% receiving EBRT. No study reported on the rates of urethral stricture
in men managed with AS. Due to the variability of urethral stricture rates reported in the
evidence, it is difficult to draw conclusions regarding the comparative safety of treatments
for this outcome.
Urinary retention
One randomised controlled trial reported urinary retention in 10% of men following
treatment with LDRBT, compared with none following RP. One study comparing
LDRBT and EBRT reported that 15% of LDRBT patients required catheterisation
following treatment, compared with none among the EBRT arm. No study reported on
the rates of urinary retention among men managed with AS.
Bowel motion frequency
One study reported an increase in men with a ‘moderate or big problem’ due to increased
frequency of bowel movements following both LDRBT and EBRT. However, at
16 months following treatment, only 2% of men treated with LDRBT continued to
report a ‘moderate or big problem’, compared with 12% of men treated with EBRT. No
study involving either RP or AS reported on frequency of bowel motions.
Faecal incontinence
One study reported an increase in faecal incontinence from baseline in 9% of men
following LDRBT and 2% following RP. However, the definition of faecal incontinence
was not reported and it is unclear whether very minor incidents were included. This is
important because infrequent and minor uncontrolled passage of faeces has little effect
on quality of life, whereas frequent or complete faecal incontinence is a major detriment
to quality of life. It is therefore difficult to draw conclusions regarding this outcome. No
study reported on faecal incontinence following EBRT or AS.
Rectal bleeding
One study reported an increase in rectal bleeding following EBRT from 8% of men at
baseline to 17% at 16 months, compared with no increase among men who received
LDRBT (remaining at 12% as per baseline). In another study a potentially contrasting
result was reported, with 15% of men who received LDRBT reporting an increase in
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rectal bleeding at 2 years. These results are difficult to reconcile. No increase in rectal
bleeding was reported among men treated with RP, and no study reported on rectal
bleeding in men managed with AS.
Erectile dysfunction
Erectile dysfunction is far more common following RP than LDRBT. Despite higher
rates of potency at baseline in men selecting nerve-sparing RP, at 3 years following
treatment 68% of men reported being unable to achieve an erection satisfactory for
intercourse, compared with 36% of men who were treated with LDRBT.
In one study no difference was reported between potency rates following treatment with
either EBRT or LDRBT. Another study that did report a difference in potency rates was
biased by patient selection and use of phosphodiesterase-5 (PDE-5) inhibitors, making
interpretation difficult.
One study reported on potency rates among men managed with AS; however, a
proportion of men were treated with EBRT, LDRBT or RP in the follow-up period and
this will impact on the potency rates.
Health-related quality of life
At times shortly following treatment, quality of life (QoL) is likely to be affected by the
side effects of that treatment. Studies reporting on comparative health-related QoL
showed mixed results, although those with longer follow-up times frequently showed no
difference between groups, or reported on small differences that are unlikely to be
clinically meaningful or noticeable to the patient.
Within 6 months following treatment, LDRBT consistently performed better than RP,
which is likely to be due to the immediate nature of RP side effects compared with the
delayed onset of some LDRBT side effects. Differences did not extend beyond 6 months
or, in two studies, better QoL was reported among RP patients. Reported differences in
QoL between men treated with LDRBT and RP were small.
Little difference in QoL was reported by studies (which reported mixed results) among
men treated with EBRT compared with men treated with LDRBT. Among studies
correcting for baseline QoL, there was no difference following LDRBT and EBRT.
QoL among men managed with AS was reported by one study and was no different from
LDRBT at 3 years following treatment.
Key uncertainties
With the exception of one randomised controlled trial, all other included comparative
studies (n=16) were cohort or matched single-arm studies. Some results have been
presented following adjustment for baseline characteristics and some studies have
matched patients on characteristics important for the prognosis of prostate cancer;
however, no study has matched patients a priori on urinary, bowel or sexual function.
The lack of homogeneity regarding function at baseline and the possible effect of patient
selection (into a treatment that will provide the best possible individual outcome in terms
of side effects) markedly affects the uncertainty surrounding the comparative safety of
treatments.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page xiii of 261
Importantly, the age of men receiving different treatments often differs substantially.
Therefore, baseline characteristics (urinary, bowel and sexual function) and the propensity
to be harmed by treatment may differ between treatment arms at the outset. This will be
particularly true for sexual dysfunction following treatment because normal erectile
function declines rapidly in men from their seventh decade onward. While erectile function
may appear to be worse following one treatment, it is possible that this is an artefact of an
ageing treatment group whose erectile function may have declined irrespective of the
intervention.
When reporting urinary incontinence, no distinction is made between possible causes of
the incontinence, which is likely to be different between surgery- and radiation-based
treatments. The nature of urinary incontinence (lack of control post surgery, obstructive
or overflow incontinence or irritative/urge) is important information as patients may wish
to avoid particular treatments that result in a type of incontinence that they are most
prone to.
When comparing studies involving EBRT and LDRBT, considerable inconsistency exists.
Whether this is a reflection of differences in treatment practice or an effect of the different
methods or tools used to measure side effects, it is likely that the differences in safety
outcomes of the two modalities are largely similar.
A lack of studies comparing outcomes following LDRBT and AS makes conclusions
about the relative safety of AS compared with LDRBT difficult.
Overall conclusion with respect to comparative safety
Urinary symptoms are common following LDRBT, EBRT and RP for localised prostate
cancer. Men receiving LDRBT or EBRT are more likely to report irritative or obstructive
urinary symptoms than men treated with RP. Irritative and obstructive symptoms abate
with time and no difference between the treatments is reported at 5 years. Urinary
incontinence is more common immediately following RP compared with LDRBT (68%
compared with 17%). Although incontinence remains more common in men following
RP at 3 years than LDRBT or EBRT, the differences between the treatments are more
modest. Urinary retention is more common following treatment with LDRBT than with
RP and more common following LDRBT than EBRT, although each of these findings is
based on single comparative studies.
Rectal bleeding is more common, and faecal incontinence may be more common,
following LDRBT than RP; however, these assertions are based on only two studies.
Bowel side effects may be fewer following LDRBT than EBRT, with most studies using
bowel-specific questionnaires reporting higher bother or worse function among EBRT
patients than LDRBT patients.
Erectile dysfunction is more common following RP than LDRBT and is unlikely to be
different between LDRBT and EBRT.
Insufficient evidence of AS was available to draw definitive conclusions regarding its
comparative safety.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Effectiveness
A total of six comparative studies reported on the primary or secondary effectiveness of
low-dose-rate brachytherapy (LDRBT) compared with external beam radiotherapy
(EBRT) or radical prostatectomy (RP). No studies were identified comparing active
surveillance (AS) with LDRBT.
Key results
Primary effectiveness
In a study examining death from any cause, actuarial 7-year survival was reported as 82%
for LDRBT, 72% for EBRT and 89% for RP. When adjusted for baseline characteristics
(such as known prognostic indicators for prostate cancer, age and comorbidities), survival
following LDRBT and RP was no different, although both were significantly greater than
survival following EBRT.
The same study reported on prostate cancer specific survival and showed little difference
between the treatment arms (97% survival for LDRBT, 94% for EBRT and 98% for RP).
This study was unable to adjust for PSA levels. Due to likely patterns of patient selection,
PSA levels would be expected to be lower in men treated with LDRBT and highest
among men treated with EBRT, and this may explain the small differences in prostate
cancer specific survival between the groups.
As the differences in overall survival among men treated with LDRBT and EBRT are
unexplained by excess prostate cancer deaths, it is likely that they are a result of unknown
or uncontrolled-for confounders rather than a true difference in treatment effectiveness.
Secondary effectiveness
Five-year freedom from biochemical recurrence (bNED) was reported by one
randomised controlled trial and found to be 91.7% and 91% among men randomised to
LDRBT and RP respectively. However, the definition used to calculate biochemical
recurrence was not reported and, as definitions differ between surgical and radiotherapy
modalities, it is uncertain whether bias may have been introduced by systematic
differences in the sensitivity or specificity of the definitions used. No other study
compared LDRBT with RP.
Studies that compared LDRBT with EBRT in terms of bNED tended to find no
difference. One study showed improved outcomes following LDRBT compared with
EBRT; however, a large proportion of men treated with EBRT in this study were
inadequately dosed.
Key uncertainties
With the exception of one randomised controlled trial involving LDRBT and RP, studies
were not randomised and confounding cannot be ruled out. Men receiving EBRT tend to
have higher risk disease and more comorbidities than men undergoing either LDRBT or
RP; therefore, differences in survival may be confounded by patient selection.
Due to the prolonged natural history of prostate cancer, often requiring more than
15 years from diagnosis to death, studies reporting on outcomes of less than 10 years may
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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not be sufficiently long to show meaningful differences (if they exist) between treatments.
One method used to forecast future outcomes is to use shorter term proxy or surrogate
outcomes, such as bNED. However, the sensitivity and specificity of biochemical
recurrence for predicting meaningful clinical outcomes such as time to metastases or
death are poorly understood. In particular, differences in definitions of biochemical
recurrence, necessitated by the different effects of surgery compared with radiation-based
therapies on PSA, may have quite disparate abilities to predict the onset of clinically
important events. Therefore, the direct comparison of bNED between surgery and
radiation therapies may also be fraught with unknown confounders.
Overall conclusion with respect to comparative effectiveness
Men who receive LDRBT or RP have better overall survival than men who receive
EBRT; however, this is unlikely to be due to differences in treatment effectiveness and
more likely to be due to confounders resulting from patient selection. Disease-specific
survival across all treatments is likely to be the same.
Five-year freedom from biochemical recurrence following LDRBT and RP is similar.
Among men who receive LDRBT and men treated with EBRT (with present day
prescriptions), 5- and 7-year bNED are similar.
Other relevant considerations
In 2007, without a systematic assessment process, the eligibility criteria for Medicare
reimbursement for LDRBT were expanded to include men diagnosed with Gleason 7
disease. The expert opinion of the Advisory Panel, in agreement with a growing body of
evidence, was that men diagnosed with Gleason score 7, whose primary Gleason grade is
4 (4+3 = 7) are at a higher risk of poor oncological outcomes compared with men whose
primary Gleason grade is 3 (3+4 = 7). Therefore, it was the intent of this current review
to assess separately the safety, effectiveness and cost-effectiveness of LDRBT for men
diagnosed with: Gleason 6 prostate cancer; Gleason 7 prostate cancer predominantly
made up of Gleason grade 3; and Gleason 7 prostate cancer predominantly made up of
Gleason grade 4.
No studies were identified that stratified men into these Gleason groups, or they did so
but rendered the Gleason 7 groups ineligible for this review due to the inclusion of
patients with other higher risk factors (ie PSA > 10 ng/mL).
Despite the absence of evidence found by this review, the Advisory Panel has
reservations about endorsing the use of LDRBT for treating men diagnosed with Gleason
4+3 = 7 disease due to the higher likelihood of extracapsular extension in this group and
the lack of international guidelines supporting treatment of Gleason 4+3 = 7 with
LDRBT as monotherapy (in the absence of adjuvant EBRT).
Economic evaluation
Three costing studies (one based in France and two in the US) reported on the
comparative costs of low-dose-rate brachytherapy (LDRBT) and radical prostatectomy
(RP). Two studies reported that costs associated with LDRBT and RP were similar, and
one study reported that costs associated with LDRBT were substantially greater. Due to
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the differences in healthcare systems, it is unclear how applicable these results are to the
Australian healthcare setting.
One health technology assessment (HTA) based in the US combined the results from
three systematic reviews of LDRBT; RP and active surveillance (AS); and intensity
modulated radiotherapy (IMRT), a form of external beam radiotherapy (EBRT). Under
the assumption of equivalent effectiveness and varying only costs and patient utility
resulting from treatment side effects, LDRBT was reported to result in 0.3 more quality
adjusted life years (QALYs) compared with RP. LDRBT was also reported to be less
expensive than RP. Compared with RP, IMRT provided 0.27 more QALYs although at a
higher cost, resulting in an incremental cost-effectiveness ratio (ICER) of $35,233. AS
resulted in 1.15 more QALYs than RP at an ICER of $1,803.
Financial impact analysis
It is estimated that 5,000 men will be diagnosed with localised prostate cancer and would
be eligible for treatment with LDRBT in 2010. The anticipated uptake of LDRBT is 1,400
in 2010, but this is likely to increase.
The differences in overall costs of each of the treatments are small. Including all nontrivial costs over 1 year, but excluding the cost of disease recurrence (assumed to be
identical across all three treatments) and of managing treatment side effects, the cost of
treating one man with LDRBT will be $12,950 if he has Gleason ≤ 6 disease and $13,800
if he has Gleason 7 disease. The increased cost associated with Gleason 7 prostate cancer
reflects the additional staging scans required following initial diagnosis. Assuming that
55% of men who are eligible for LDRBT have Gleason ≤ 6 prostate cancer, the average
cost of LDRBT is $13,322 per patient. The average cost of treating one man with EBRT
is $13,428, and to treat one man with RP will cost $13,286.
The annual cost to the MBS of treating one-third of the 5,000 potentially eligible men
with LDRBT, one-third with EBRT and one-third with RP would be $28.362 million.
The cost to the MBS of providing LDRBT is substantially less than for EBRT, but this
cost saving is entirely attributable to the redistribution of costs to other sectors of the
Australian healthcare system.
Overall annual costs to the Australian healthcare system for treating one-third of the
5,000 potentially eligible men with LDRBT, one-third with EBRT and one-third with RP
is $66.727 million. As the overall costs of providing LDRBT are similar to those for
EBRT and RP, and men are equally likely to be drawn from each of these competing
treatments, the financial impact of continued listing of LDRBT on the MBS is minimal.
The cost of providing AS is largely contingent upon the number of men who opt for, and
persist with, this treatment. AS may be inappropriate for men with Gleason 7 prostate
cancer, and therefore it has been costed only for men with Gleason ≤ 6 disease. The best
estimate for the use of AS in this population in Australia is 20%. Assuming that 57% of
men who select AS will proceed to active treatment over 10 years, the discounted annual
cost of treating 5,000 men with LDRBT, RP, EBRT or AS is estimated at
$65.684 million. If the uptake of AS increases, or the transition to active treatment
decreases, the overall cost of managing 5,000 men with localised prostate cancer will be
reduced.
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Introduction
Adelaide Health Technology Assessment, with input and advice from an appropriately
constituted Advisory Panel of experts (see Appendix B), has reviewed the use of lowdose-rate (LDR) permanent seed brachytherapy (BT) for the treatment of early localised
prostate cancer.
This assessment report is intended for the Medical Services Advisory Committee (MSAC).
The MSAC evaluates new and existing health technologies and procedures for which
public funding is sought in terms of their safety, effectiveness and cost- effectiveness,
while taking into account other issues such as access and equity. The MSAC adopts an
evidence-based approach to its assessments, based on reviews of the scientific literature
and other information sources, including clinical expertise.
This report summarises the assessment of current evidence on LDR permanent seed BT
for the treatment of early localised prostate cancer. It updates and expands upon two
previous MSAC assessments (Medical Services Advisory Committee 2000 and Medical
Services Advisory Committee 2005).
Rationale for assessment
This review of Application 1089 is a reference from the Australian Department of Health
and Ageing to the MSAC to have an assessment undertaken of the safety, effectiveness
and cost-effectiveness of LDR 125I BT for the treatment of localised prostate cancer. The
MSAC assessment (1089) in 2005 recommended continued interim public funding for
LDRBT for the treatment of prostate cancer. The Minister for Health and Ageing
accepted this recommendation on 28 November 2005. This current assessment updates
the previous two MSAC assessments published in 2000 and 2005, so that the interim
funding recommendation can be reviewed.
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Background
Previous MSAC assessments
Initial MSAC assessment 1029
The initial MSAC review of the safety, effectiveness and cost-effectiveness of iodine-125
(125I) LDRBT for prostate cancer was undertaken in 2000 (MSAC application number
1029). This review compared LDRBT as a treatment for early, localised prostate cancer
with those treatments then in use in Australia: radical prostatectomy (RP), external beam
radiotherapy (EBRT) and active surveillance (AS). The assessment was unable to identify
any randomised controlled trials (RCTs) comparing the effectiveness of treatments, and
conclusions were therefore based on level III and level IV evidence.
The recommendation for interim funding for men with localised prostate cancer, with
Gleason scores of 6 or less and with a prostate specific antigen (PSA) of 10 ng/mL or
less, was accepted by the Minister for Health and Aged Care on 9 February 2001.
MSAC review 1089
In 2005 the MSAC re-reviewed LDR 125I BT as a treatment for early, localised prostate
cancer incorporating new evidence generated since the initial review. The evidence
available for this review was not strong (level III) and the lack of RCTs precluded
substantive conclusions regarding the safety and effectiveness of LDRBT in comparison
with RP, EBRT or AS. The report found that there was no evidence available that
demonstrated a difference in survival or disease progression between LDRBT, RP and
EBRT. Furthermore, there were no studies directly comparing either survival or disease
progression in men treated with LDRBT or AS. Low-level evidence (level III-2) suggested
that LDRBT may be comparable to, or better than, RP or EBRT in terms of sexual
functioning following treatment, as well as resulting in lower rates of post- treatment
incontinence. It was reported that LDRBT may result in higher rates of lower urinary
tract (irritative or obstructive) symptoms than EBRT, and higher or comparable rates of
rectal side effects compared with EBRT based on a small number of included studies.
Faecal incontinence was potentially higher in patients treated with LDRBT compared
with those treated with RP. Limited evidence (level III-2) reported that overall quality of
life at 1 year post treatment was comparable for LDRBT and RP.
Direct costs of LDRBT compared with RP and EBRT, were estimated using current
Australian pricing of staff, procedures and materials required for each treatment option.
The adverse event rates and associated utilities, modelled into quality adjusted life years
(QALYs), were taken from a cost-effectiveness model (Hummel et al 2003) generated on
behalf of the National Institute for Health and Clinical Excellence (NICE). Incremental
QALYs for LDRBT versus AS were small, estimated at 0.55 compared with 0.26 for RP
and –0.05 for EBRT. These were based on the assumption of equivalent patient survival.
However, LDRBT was more costly than either RP or EBRT. Incremental cost
effectiveness ratios (ICERs—cost per QALY) were not reported due to the variability of
the ICER estimates in the sensitivity analyses.
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These findings, in combination with the findings of the initial MSAC assessment, led to
the MSAC’s recommendation to continue interim funding at approved sites for LDRBT
in the treatment of men with early localised prostate cancer. This recommendation was
accepted by the Minister for Health and Ageing in 2005.
MBS amendment July 2007
In 2006 an application was submitted to the Department of Health and Ageing by the
Australian and New Zealand Association of Urological Surgeons (ANZAUS) citing
studies supporting the expansion of the eligibility criteria for LDRBT to include patients
with a prostate cancer Gleason score of 7. No other alteration to the eligibility criteria was
sought. Primarily, the argument for including patients with Gleason scores of 7 on biopsy
related to the upward migration of Gleason scores in recent times, such that a proportion
of Gleason 6 patients considered by earlier MSAC reviews would, were they regraded in
2006, be scored as Gleason 7 (which would render them ineligible for LDRBT).
The NHMRC Clinical Trials Centre (CTC) undertook a critique of the evidence
presented in the ANZAUS submission, and found a consistent pattern supporting the
change in histopathological scoring of prostate cancer resulting in an increased
assignment to Gleason 7. It was concluded that the studies reviewed supported the
proposal for increasing the Gleason score cut-off for LDRBT to 7. This recommendation
was accepted by the Minister for Health and Ageing, and the criteria for MBS item
numbers 37220 and 15338 were amended in July 2007 (Medicare Australia 2007).
However, the evidence presented by ANZAUS was non-systematically obtained and the
assessment by CTC was not considered to be equivalent to a full systematic review. An
evidence-based decision regarding this subpopulation is particularly important as it is
likely to result in a substantial increase in the proportion of patients eligible for Medicare
reimbursement for LDRBT in Australia.
This review will consider evidence published since 2005 and update the findings of the
previous two MSAC assessments (1029 and 1089) for the patient cohort described before
the change in reimbursement criteria (ie Gleason score ≤ 6). In addition, this review will
consider all evidence from 2000 for the subpopulation that was excluded from previous
MSAC assessments but have been eligible for MBS-funded LDRBT since 2007 (ie
Gleason score = 7).
Brachytherapy
The procedure
LDRBT (also known as permanent interstitial radiotherapy or seed BT) is the
implantation of radioisotopes (iodine-125 or palladium-103) directly into the prostate
gland. The implantation is carried out under transrectal ultrasound guidance and can be
performed as a day-patient procedure, although it usually involves at least an overnight
stay. The radioactive sources are distributed throughout the prostate according to
planning done pre- or intra-operatively to ensure adequate coverage of radiation (emitted
as X- and gamma rays) for the ablation of tumour cells. BT seeds have a local effect, with
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a sharp dose fall-off, governed by the inverse square law, resulting in adjacent tissues
receiving only very low doses of radiation.
LDRBT is performed using either palladium-103- (103Pd) or iodine-125- (125I) filled
titanium seeds. While 125I and 103Pd decay at different rates, there is insufficient evidence
to show that the isotopes result in different patient outcomes. However, this remains a
possibility and, as only 125I seeds are available in Australia, data from studies using 103Pd
have not been considered in this review. Seeds may be delivered as single units or
attached by absorbable sutures in strands. Some studies have shown that stranded seeds
have a lower incidence of seed loss or migration to structures outside the prostate (AlQaisieh et al 2004; Reed et al 2007).
LDRBT in Australia is delivered via the perineal percutaneous route. Historically, 125I
seeds were placed using a retropubic approach (Carlton et al 1972; Whitmore et al 1972),
often accompanied by pelvic lymph node dissection, which was associated with poorer
outcomes (Fowler et al 1979; Zelefsky & Whitmore 1997). Only current methods of
relevance to practice in Australia will be considered as part of this review.
Iodine-125 has a half-life of 60 days, and decays to tellurium-125 via an excited state of
tellurium-125, emitting photons of various energies as well as Auger electrons. The most
abundant photon emission is a 27 keV X-ray. Each seed typically has an activity of 11–
15 MBq (0.3–0.4 mCi), and seeds are distributed to achieve a prescribed dose of 145 Gy
to the planning volume. Post-implant dosimetry is performed by imaging of the prostate
and the 125I seeds to confirm adequate coverage, and that an acceptable dose has been
delivered to the planned region. An excellent dose distribution occurs when the
proportion of the prostate that receives the full prescribed dose nears 100% without
adjacent structures receiving unacceptably high doses of radiation. Currently, the total
radiation dose to the prostate from LDRBT (145 Gy) is numerically about twice that
from conventional EBRT (typically 70–80 Gy), with a somewhat greater biologically
effective dose to tumour and prostate tissue (Lehnert et al 2005), and lower doses to
surrounding tissue.
Whether prostate size or pubic arch interference are contraindications to LDRBT is
uncertain, and has been refuted by Merrick and Wallner et al (2004) and the American
Brachytherapy Society (Merrick et al 2004; Nag et al 1999). However, large prostates are
reported as a relative contraindication, with the best results attained only from
experienced brachytherapists. LDRBT may be given to individuals with large prostates if
a short (3–6 months) course of adjuvant androgen deprivation therapy, usually luteinising
hormone-releasing hormone (LHRH) agonists, is administered. This acts to decrease the
tumour and prostate volume to a more acceptable range. In higher risk patients, LDRBT
may be combined with EBRT; however, only LDRBT as a monotherapy is being assessed
in this review.
The LDRBT procedure involves a urologist, radiation oncologist, medical physicist,
radiation therapist and anaesthetist. Sophisticated planning software and imaging
technology are required for the implantation and post-implant dosimetry. Implants that
are found to have inadequately dosed the prostate in some areas may be ‘topped up’ with
further seeds, requiring a second procedure or using subsequent EBRT (Stock & Stone
2002).
LDRBT is proposed to be an efficient, effective and safe treatment for men with early,
localised prostate cancer. The in-hospital duration (1–2 days) is shorter than the usual
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EBRT outpatient daily regimen of 7+ weeks. Survival following LDRBT is considered by
some to be equivalent to EBRT and RP, with a different adverse event profile more
acceptable to some patients (ie potentially with lower rates of erectile dysfunction and
incontinence than RP). However, according to the previous MSAC assessment (1089),
LDRBT is currently more expensive and may be associated with different complications.
The proposed benefits and costs are investigated further in subsequent sections of this
assessment.
Intended purpose
LDRBT as a monotherapy is intended for use in the treatment of early localised prostate
cancer. Current Australian clinical practice guidelines for the management of localised
prostate cancer (Australian Cancer Network Working Party 2002) recommend LDRBT
for patients with ‘localised prostate cancer of low volume with Gleason score < 7 and
greater than a 10-year life expectancy’. This recommendation was reinforced in the
previous 2005 MSAC review (1089). The MSAC’s indications for the use of LDRBT
following the 2005 review are listed below:
 clinical stages T1 and T2
 Gleason score ≤ 6
 prostate specific antigen ≤ 10 ng/mL
 prostate gland volume less than 40 cc
 life expectancy ≥ 10 years.
In July 2007 eligibility criteria for medical benefits reimbursement were amended to
include patients with Gleason scores of 7.
These indications are similar to those recommended by most international agencies
(American Brachytherapy Society (ABS) 2007; American Urological Association (AUA)
2007; European Association of Urology (EAU) 2009; National Comprehensive Cancer
Network (NCCN) 2010; National Institute for Health and Clinical Excellence (NICE)
2008), as presented in Table 1.
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Table 1
Indications for low-dose-rate brachytherapy according to international guidelines
Indications
EAUa
AUAb
NCCNc
NICEd
ABSe
Clinical stage
T1b–T2a
T1c–T2a
T1–T2a
T1–T2c
T1b–T2b
Gleason score
≤ 6 (or 3+4)f
≤6
≤6
≤7
≤6
Prostate specific
antigen (PSA)
≤ 10 ng/mL
≤ 10 ng/mL
< 10 ng/mL
< 20 ng/mL
≤ 10 ng/mL
Gland volume
< 50 cc
-
-
-
-
Life expectancy
> 10 yearsg
-
≥ 10 years
-
> 5 years
IPSS
Good (0–8)
-
-
-
-
Dose (125I)
145 Gy
-
145 Gy
-
145 Gy
Other
No previous
TURPh
< 50% biopsy
cores positive
Large and very
small prostates
or poor IPSSi
are contraindicated
Evidence of N or
M diseasej,
inflammatory
bowel disease
and extensive
TURP defects
are contraindicated
European Association of Urology (EAU); b American Urological Association; c National Comprehensive Cancer Network; d National
Institute for Health and Clinical Excellence; e American Brachytherapy Society; f The appropriateness of brachytherapy for Gleason 3+4
is presented as uncertain in the EAU guidelines; g a condition for all definitive therapy in these guidelines and not explicitly stated as a
condition of brachytherapy; h transurethral resection of the prostate; i International Prostate Symptoms Score; j nodal (N) or metastatic
(M) disease
a
Defining the target population
Staging and grading of prostate cancer is central to disease prognosis and therefore
treatment choice. Strategies for determining the stage, grade and likelihood of the
presence of adverse features of prostate cancer are discussed below. This evaluation of
LDRBT is restricted to patients with localised (stages T1–2), well to moderately
differentiated (Gleason ≤ 7) cancer with a PSA ≤ 10 ng/mL.
Tumour–nodes–metastases staging
The tumour–nodes–metastases (TNM) staging system describes the extent of tumour in a
patient’s body. The tumour (T) staging describes the size of the tumour and whether it
has invaded adjacent structures; the nodal (N) staging describes the involvement of
regional lymph nodes; the metastases (M) staging describes distant spread of the tumour,
such as to other organs or bone. The TNM staging system is managed by the
International Union Against Cancer (UICC—Union Internationale Contre le Cancer) and
is a globally recognised method for describing the extent of cancers. The most recent
edition was released in 2009 (Sobin et al 2009), and an explanation of this staging system
is presented in Table 2.
In prostate cancer, tumour staging is a clinical judgement based on the digital rectal exam
and available imaging, such as ultrasound or magnetic resonance imaging (MRI). Nodal
staging is assessed by means of computerised tomography (CT) or MRI scan. Prostate
cancer guidelines usually recommend against the use of CT scans in the staging of men
with low-risk prostate cancer; however, these scans may be used in the course of LDRBT
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for planning purposes (Krempien et al 2003). Staging of skeletal metastases is assessed by
whole-body radionuclide bone scanning although, once again, bone scans may not be
warranted in patients deemed to be at low risk (American Urological Association (AUA)
2007; European Association of Urology (EAU) 2009; National Institute for Health and
Clinical Excellence (NICE) 2008).
Table 2
UICCa tumour–nodes–metastasis staging system for prostate cancer
Classification
Definition
T classification
Primary tumour
Tx
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Clinically inapparent tumour, not detected by digital rectal examination or visible by imaging
T1a
T1b
T1c
T2
Incidental histological finding; ≤ 5% of tissue resected during TURP
Incidental histological finding; > 5% of tissue resected during TURP
Tumour identified by needle biopsy
Tumour confined within the prostate
T2a
Tumour involves half of one lobe or less
T2b
Tumour involves more than half of one lobe but not both lobes
T2c
Tumour involves both lobes
T3
Tumour extends through the prostate capsule but has not spread to other organs
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumour invades seminal vesicle(s)
T4
N classification
Tumour is fixed or invades adjacent structures other than seminal vesicles
Regional lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M classification
Distant metastases
M0
No distant metastases
M1
Distant metastases
a
Sobin et al (eds) 2009
Gleason score
The Gleason score is a histopathological system used for grading the degree of
differentiation of prostate cancer cells. The score is made up of the sum of two scores—
the first representing the grade of the most prevalent tumour cells and the second the
grade of the next most prevalent tumour cells (comprising at least 5% of the tumour
examined). Each tumour score is out of 5, with 1 being well differentiated and 5 being
undifferentiated, thus giving a possible minimum score of 2 and a possible maximum
score of 10. As a prognostic variable, Gleason scores of less than 7 are usually deemed
low risk, 7 are intermediate risk, and greater than 7 are high risk in the absence of other
adverse prognostic factors.
Good evidence suggests that patients with a Gleason score of 7 but with a preponderance
of Gleason grade 3 (ie 3+4 = 7) experience better prognoses than those with a
preponderance of Gleason grade 4 (ie 4+3 = 7) (Chan et al 2000; Kang et al 2007;
Khoddami et al 2004; Lau et al 2001; Makarov et al 2002; Rasiah et al 2003). Importantly,
tumours with Gleason scores of 4+3 = 7 may behave more like tumours with scores of
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4+4 = 8 than tumours with scores of 3+4 = 7 (Kang et al 2007). In addition, 4+3 = 7
tumours, which are clinically inapparent with PSA 6.1–10.0 ng/mL, remain organ
confined in only 43 % of cases [95% CI: 35-51], compared with 54% of cases [95% CI:
49-59] for 3+4 = 7 tumours (Partin et al 2001).
The differences in risk and likelihood of spread beyond the prostate for Gleason scores
3+4 and 4+3 may have important ramifications for the appropriateness of prostate
cancer treatments. LDRBT, in particular, is a localised treatment with little effect beyond
the prostate due to the rapid dose fall-off from the BT seeds.
Prostate-specific-antigen (PSA)
PSA is a protein produced by the prostate that is present in the blood. Many different
processes in the prostate may lead to a raised PSA level (eg infection, benign hypertrophy
or cancer), but it has long been used as a marker for the presence of prostate cancer (Aus
et al 2005; Gann et al 1995; Stenman et al 1994), a predictor of tumour stage (Pinsky et al
2007; Stamey et al 1987) and a prognostic marker for patient outcomes, as shown by its use
in almost all prostate cancer risk assessment tools (Cooperberg et al 2005; D’Amico et al
2007; Kattan et al 1998; Stephenson et al 2005).
As PSA testing becomes more widespread and patients are diagnosed with earlier stage
and possibly clinically irrelevant cancer, PSA may become a less important predictor of
adverse pathological findings (Stamey et al 2004). This trend, however, has had little
effect on the use of PSA to classify risk, and it remains an important marker of nodal or
distant disease at higher levels (Catalona & Loeb 2005).
Contraindications
LDRBT is contraindicated in those patients:
 with a history of extensive transurethral resection of the prostate (TURP)
The American Brachytherapy Society states that a large TURP defect can be technically
difficult to plan and results in a heightened chance of loss of seeds, and that patients may
be at a greater risk of harmful outcomes (Nag et al 1999).
 who have pre-treatment obstructive urinary symptoms
The European Association of Urology recommends against using LDRBT in patients
with an International Prostate Symptoms Score (IPSS)1 of ≥ 8 (Ash et al 2000), as these
patients may be at greater risk of obstruction following the procedure.
 with prostates larger than 50 cc
Large prostates may be difficult to access via the perineal route and be associated with
higher rates of urinary retention following seed implantation (Ash et al 2000). Adjuvant
androgen deprivation therapy (ADT) may be used to reduce the prostate to a more
appropriate size; however, the harms associated with ADT should be considered.
IPSS measures irritative and obstructive urinary symptoms such as incomplete emptying, urinary
frequency, intermittency, urgency, weak stream, straining and nocturia.
1
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
 with intermediate- or high-risk prostate cancer
Definitions of intermediate-risk prostate cancer vary, although it usually includes men
with a Gleason score ≥ 7 or PSA > 10 ng/mL or clinical stage T2b–c (D’Amico et al
1998; National Comprehensive Cancer Network (NCCN) 2010). The National Institute
for Health and Clinical Excellence (NICE) guideline for prostate cancer (2008) is the only
current guideline that does not specifically advise against LDRBT (delivered as
monotherapy) for patients with intermediate-risk prostate cancer (see Table 1). However,
the NICE guidelines appear to be for both LDRBT delivered as monotherapy and with
an EBRT boost. Therefore, with the exception of the NICE guideline for prostate cancer,
the Australian reimbursement for LDRBT as monotherapy for patients with
intermediate-risk prostate cancer (Gleason 7 disease and clinical stage T2c) appears
unique.
Follow-up
Follow-up or monitoring after treatment for localised prostate cancer is primarily used to
identify and treat complications of radical treatment, identify early disease progression for
which further adjuvant or salvage therapy may still be effective, and audit the outcomes
of treatment (National Institute for Health and Clinical Excellence (NICE) 2008).
Follow-up should continue for at least 2 years, and men who have no ongoing significant
treatment complications should be offered follow-up in primary care or via telephone.
PSA levels should be recorded at least 6-monthly for 2 years, and at least yearly thereafter
(National Institute for Health and Clinical Excellence (NICE) 2008).
PSA monitoring following radical treatment may help provide an indication of treatment
failure. If treatment failure is identified early, additional radical treatment may be
prescribed. However, further treatment based solely on PSA-assessed recurrence is of
questionable merit (McLeod 2005). The use of a post-treatment PSA increase
(biochemical recurrence (BR)) by investigators as a surrogate outcome for survival or
cancer progression is common, although is fraught with problems (Kuban et al 2004).
Definitions of BR vary across and within treatments, and across time periods. Recently,
BR following radiotherapy has been defined as a rise of 2 ng/mL above the nadir2
(Abramowitz et al 2008) and has replaced the previous American Society for Therapeutic
Radiology and Oncology (ASTRO) definition that required three consecutive rises3. The
newer definition has been shown to be a better surrogate for disease progression, overall
survival and disease-specific survival (Kuban et al 2006; Roach et al 2006). However, there
has been some criticism of the false positive identification of BR in men who receive
LDRBT (Thompson et al 2010). In addition, BR lacks specificity and so a far greater
number of men experience treatment failure according to PSA measures than do men
who progress or die of prostate cancer (Jhaveri et al 1999; Pound et al 1999). Given
that BR is measured differently in men who undergo RP, and is impossible to interpret in
men who select AS, BR may be a poor surrogate measure for treatment effectiveness,
particularly when comparing modalities. A more accurate measure would be diseasespecific or all-cause survival. The drawback of not having an appropriate surrogate
marker for survival in men with early localised prostate cancer is that the disease can be
2
3
Commonly referenced as the ‘Phoenix’ definition.
Commonly referenced as the ‘ASTRO’ definition.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 9 of 261
indolent or very slow to progress. Pound et al (1999) reported that the median time to
metastatic disease following BR was 8 years, although this was closer to 10 years in men
with Gleason scores < 7. It was then a median of 5 years from the development of
metastases to death. As such, expensive long-term trials are required to study the
outcomes of treatments for low-risk prostate cancer patients, and often technologies alter
before definitive results are available. LDRBT in its current form has not been available
for sufficiently long to generate meaningful survival evidence.
Assessment of adverse events
All accepted forms of treatment for prostate cancer involve side effects. However, the
nature and severity of side effects may differ from treatment to treatment, and the tools
used to measure side effects also vary. The American Brachytherapy Society recommends
that studies of LDRBT use the IPSS, the International Index of Erectile Function (IIEF)
and the Radiation Therapy Oncology Group (RTOG) toxicity grading criteria to record
urinary, sexual and bowel symptoms respectively. Unfortunately, the IPSS records irritative
or obstructive urinary symptoms, which are common in radiotherapy modalities, yet does
not record incontinence or urinary control, which is a far greater complaint following RP.
This results in difficulties when comparing patient outcomes across modalities. In
addition, the tools are often used to report symptoms at a defined time following
treatment with little regard for pre-treatment morbidity. This can be problematic,
particularly as the population who tend to be diagnosed with prostate cancer also tend to
be older and therefore have a higher rate of baseline (pre-treatment) urinary, sexual or
bowel symptoms.
Comparisons between treatments with disparate side effect profiles, such as LDRBT and
RP, are complicated by differences in consumer preference. Patients may accept an
increased risk of some adverse events if a treatment minimises the risk of less desirable
adverse events, although which side effects are less desirable will be specific to the patient.
Therefore, measures that convert certain health states, such as erectile dysfunction or
urinary incontinence, to broad metrics such as QALYs can only do so by accepting a
mean measure, and may inadequately reflect the importance of certain health states (or
avoiding certain health states) in individuals.
Clinical need / burden of disease
Natural history of early localised prostate cancer
Prostate cancer is a heterogeneous disease encompassing a continuum of clinical
outcomes. Some patients will experience rapid disease progression, while others may live
with prostate cancer for many years only to die of an unrelated illness. Figures from
Australia estimate that as many as one in five men will be diagnosed with prostate cancer
by the age of 85 years, yet it will account for only about 4% of all male deaths (Australian
Institute of Health and Welfare (AIHW) 2009a).
A population-based cohort study of men in Sweden that studied 223 patients diagnosed
with localised prostate cancer who were treated conservatively reported consistently low
mortality rates (average 15/1,000 person years) until 15 years following diagnosis
(Johansson et al 2004). This represents a disease-specific survival for all patients of nearly
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80%. At the same time point, overall survival was marginally greater than 20%, a
reflection that the vast majority of men had died of unrelated causes. The authors report a
decrease in disease-specific survival over the following 5 years to 54.5%; however, this
change is based on very small numbers (8 deaths from prostate cancer). This study
highlights that early localised prostate cancer follows, in most cases, an indolent course,
requiring many years before death due to prostate cancer. It is important to note that the
Johansson study recruited patients from 1977 until 1984, a period that pre-dates the use
of PSA testing, which has subsequently altered prostate cancer detection rates and time to
event analyses. In addition, all cancer grades were included, and many of the prostate
cancer deaths were among men with higher grade cancers.
With the advent of PSA testing, the proportion of men who are diagnosed with prostate
cancer has risen sharply, reflecting an increased diagnosis of clinically irrelevant cancers.
In addition, PSA testing has introduced, in many men, a lead time of about 10 years
(Draisma et al 2003) before symptoms or clinical examination may have led to a
diagnosis, therefore complicating comparisons of survival between historical (pre-PSA)
studies and contemporary studies, and between studies from countries with disparate
rates of PSA testing.
At present it is not possible to differentiate clinically irrelevant cancers from those that
will progress to cause morbidity or death. Draisma et al (2003) estimated that, with the
advent of PSA screening, detection of clinically insignificant cancers may be as high as
50%. Until a useful marker is discovered to identify those patients who will benefit from
treatment, it is important to ensure that any treatment given (particularly in patients with
low-risk tumours) balances the low likelihood of progression and death with the potential
for adverse events and changes in quality of life imposed by the treatment.
Epidemiology
Incidence and mortality rates
Prostate cancer is the most commonly diagnosed cancer in Australian men (excluding
non-melanocytic skin cancer) and the most common cancer diagnosed in Australians
overall (men and women), followed by colorectal cancer and breast cancer. Prostate
cancer is the second leading cause of cancer deaths in men after lung cancer (Australian
Institute of Health and Welfare (AIHW) & Australasian Association of Cancer Registries
(AACR) 2008).
In 2006 there were 17,444 new cases of prostate cancer and 2,971 deaths attributed to
prostate cancer among Australian men (Australian Institute of Health and Welfare
(AIHW) 2009a). These numbers represent 29.5% of all male cancers and 13.3% of all
male cancer deaths for 2006. The incidence rate has been steadily rising in Australia since
2000 following a decline from its peak in 1994 of 184.3 per 100,000 males (age
standardised to the Australian Standard Population 2001). The sudden increase of
diagnoses in Australia in the early to mid 1990s most likely reflects the introduction of
PSA testing and mirrors a trend that occurred in the US about 3 years earlier. In 2006 the
age-standardised incidence rate for prostate cancer in Australian men reached 170.0 per
100,000 males.
Despite increases in incidence, cancer-specific mortality has fallen to 31.0 deaths per
100,000 Australian men in 2007 from more than 40 per 100,000 in the mid 1990s. This
may reflect the benefits of earlier detection, effective radical treatment and life-prolonging
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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interventions such as ADT. The high death rates in the mid 1990s may also be due to bias
related to the misattribution of cause of death (Collin et al 2008). The 5-year relative
survival rate of men with prostate cancer has increased from 57% in the period 1982–86 to
85% in 1998–2004 (Australian Institute of Health and Welfare 2008). However, this trend
is probably the result of over-diagnosis and the introduction of lead time bias due
to the use of PSA testing. Irrespective of the degree of over-diagnosis of prostate cancer,
absolute numbers of men dying from the disease outnumber deaths due to breast cancer.
With the advent of PSA testing, the average age at diagnosis of prostate cancer has fallen
from 73 years in 1982 to 69 years in 2006; however, it remains a very rare disease in men
younger than 50 years of age. The lifetime risk of developing prostate cancer before the
age of 75 years now stands at about one in seven; by the age of 85 years, it is expected
that one in every five men will have a prostate cancer diagnosis.
While age at diagnosis continues to fall, prostate cancer mortality continues to occur later
in life, with an average age at death of 78.6 years in 2006. Consequently, despite its
prevalence, prostate cancer has a lower overall burden of disease when measured by
potential years of life lost (PYLL) compared with other cancers. In 2006 prostate cancer
resulted in 6,413 PYLL compared with 45,958 PYLL for lung cancer (Australian Institute
of Health and Welfare (AIHW) 2009d), 23,380 PYLL for colorectal cancer (Australian
Institute of Health and Welfare (AIHW) 2009c) and 27,230 PYLL for breast cancer
(Australian Institute of Health and Welfare (AIHW) 2009b). However, it should be noted
that this measure may be flawed given that the PYLL beyond 75 years of age are not
accounted for in this database, yet the average additional life expectancy of a man at the
age of 50 years is 31.4 years compared with 14.7 years for a man at the age of 70 years
(Australian Bureau of Statistics 2008). This will result in a relative underestimation of the
PYLL among prostate cancer patients, who have a propensity to live to an older age than
other cancer patients.
Potential utilisation
LDR 125I BT for the treatment of localised prostate cancer is currently listed on the MBS
for men with PSA < 10 ng/mL, Gleason score ≤ 7 and a clinical stage of T1 or T2.
Predicting the potential utilisation of LDR 125I BT is difficult given the lack of published
national epidemiological data stratifying Australian prostate cancer patients by stage or
grade. Recently, data from the South Australian (SA) cancer registry spanning 1998–2006
was found to be broadly comparable with an SA-based prostate cancer outcomes
database that captured approximately 20% of prostate cancer diagnoses state-wide
(Beckmann et al 2009). From a cohort of 2,329 patients, about 34% were found to be at
low or intermediate risk and younger than 70 years of age at diagnosis. If this finding
were generalisable to the Australian population, more than 5,000 men diagnosed in 2006
would potentially be eligible for LDRBT. However, not all intermediate risk patients from
Beckmann et al (2009) are currently eligible for LDRBT, as some have PSA levels
> 10 ng/mL.
In a large New South Wales (NSW)-based cohort study of 1,642 men younger than
70 years of age and diagnosed with localised (T1 or T2) prostate cancer during October
2000–02 (Smith et al 2010), nearly 90% were found to have a Gleason score of 7 or less,
and nearly 70% were found to have a PSA of < 10 ng/mL. If the patients who refused
consent (n=627) and the patients of those doctors who refused to participate (n=537)
had a similar distribution of Gleason score and PSA, at least 1,800–2,000 men would have
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been diagnosed with localised, Gleason score ≤ 7, PSA ≤ 10 ng/mL prostate cancer
between 2000 and 2002. Data collection occurred over 2 years; thus, approximately 1,000
men from NSW may have been eligible for LDRBT in 2001 or 2002. Given that the
incidence of prostate cancer has increased nearly 50% to 2006, 1,500 men from NSW
may have been eligible in 2006 for LDRBT. The average annual incidence of prostate
cancer in NSW between 2001 and 2005 represented about one-third of all incident
prostate cancer cases in Australia. Therefore, based on 2006 rates, approximately 4,500
men Australia-wide may have been eligible for LDRBT. This calculation is in agreement
with the estimation from the Beckman et al (2009) study above, and therefore an estimate
of 5,000 men per year has been used for costing in subsequent sections of this
assessment.
As rates of opportunistic PSA testing rise, numbers of patients eligible for LDR 125I BT
are also likely to rise, given that PSA levels at diagnosis will fall and more patients will be
diagnosed with prostate cancer at a younger age. This is strongly supported by Australian
Institute of Health and Welfare (AIHW) data, which show that the risk of being
diagnosed with prostate cancer for men aged 80–84 years has not changed since 1982,
whereas the risk of being diagnosed at younger than 65 years has increased from 1 in 111
in 1982 to 1 in 18 in 2006. While prostate cancer incidence has risen over the past
3 decades, the majority of this growth of incidence has occurred in younger men.
There are additional preconditions for LDR 125I BT that incorporate gland volume and
urinary function; however, these are not likely to exclude substantial proportions of men
from treatment with LDRBT, particularly if the age at diagnosis continues to decrease.
The proportion of men who will actually receive LDRBT is limited by factors other than
eligibility. Over recent years the observed number of LDRBT procedures has likely been
limited by access to these services, patient choice for competing treatment options and
cost implications.
Table 3
Item numbers and utilisation for prostate brachytherapy and open prostatectomy
Procedural Code
Source
MBS number – 15338:
PROSTATE, radioactive
seed implantation of
AIHW
Medicare
1167: Open Prostatectomy
AIHW
2001–
02
2002–
03
2003–
04
2004–
05
2005–
06
2006–
07
2007–
08
Count
-
-
-
536
663
734
968
Same day (%)
-
-
-
9.3
11.6
14.2
16.4
Count
46
136
224
305
376
390
687
Count
3,003
3,413
4,357
5,347
5,521
6,569
7,041
Sources: AIHW (2010) and Medicare Australia (2010)
In the 2007–08 financial year there were 968 recorded procedures associated with MBS
item number 15338, which is specific to permanent 125I BT for prostate cancer. Table 3
shows the steady increase in LDRBT procedures for prostate cancer since 2001 following
the initial MSAC recommendation for interim funding. The AIHW data are sourced from
the National Hospital Morbidity Database and are an accurate representation of the
number of LDRBT procedures from 2004 onward. Before 2004 the database does not
separate out other interstitial LDRBT procedures from prostate-specific procedures, and
thus the data are unreliable. The Medicare data represent only those procedures that have
attracted a Medicare reimbursement and therefore do not capture procedures for public
patients in public institutions. Also, in Table 3 the AIHW data show an increasing
proportion of patients that are flagged as having received ‘same day’ procedures.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 13 of 261
Over the same period there has been a similar increase in RPs. Table 3 shows the number
of open prostatectomies (ICD-10AM code 1167) performed. This may underestimate the
true number due to the recent increase in robot-assisted laparoscopic prostatectomies in
Australia. Not all patients who are candidates for prostatectomies are eligible for LDRBT;
however, it is likely, if trends observed in the US (Cooperberg et al 2004) are mirrored in
Australia, that LDRBT will increasingly replace RP as a treatment choice for patients with
low-risk prostate cancer.
Existing procedures
The management of localised prostate cancer remains controversial. To date, there have
been few studies that compare present-day treatments; consequently, most established
treatments are considered to be equally effective. Early diagnosis resulting in many years’
lead time and the long natural history of prostate cancer can make true measures of
treatment outcomes difficult to ascertain in the short term. New treatments for prostate
cancer may take more than a decade to adequately assess in terms of cancer control. In
Australia the most commonly used options for managing localised prostate cancer are
radical prostatectomy (RP), external beam radiotherapy (EBRT), brachytherapy (BT) and
deferred treatment (active surveillance (AS)).
Comparators
Radical prostatectomy
RP is the surgical removal of the prostate gland and reconnection of the urethra to the
bladder neck. It can be performed as an open procedure, either using a retropubic or
perineal approach, or laparoscopically. The more common of the two open techniques is
the retropubic, requiring an abdominal incision that allows concomitant removal of pelvic
lymph nodes (lymphadenectomy). Retropubic prostatectomy became the standard
approach in the 1980s after Patrick Walsh performed the first nerve-sparing
prostatectomy (Eggleston & Walsh 1985). Radical perineal prostatectomy, which involves
a small incision between the ischial tuberosities, tends to be a shorter operation with less
blood loss, although identification and sparing of the neurovascular bundles is technically
more difficult. If lymphadenectomy is required, a separate abdominal incision for open or
laparoscopic removal can be used.
Laparoscopic prostatectomy and, more recently, robotic-assisted laparoscopic
prostatectomy require several small incisions in the abdomen, into which a camera and
surgical instruments are passed. The robotic-assisted laparoscopic approach involves a
surgeon operating from a remote console by manipulating miniature robotic ‘arms’ and
viewing the procedure rendered in three dimensions by dual fibre optic cameras. Both
laparoscopic and robotic-assisted procedures tend to be minimally invasive and may
result in reduced blood loss and reduced recovery time, and with comparable oncological
outcomes, compared with the open approach (Rassweiler et al 2003).
RP is a major surgical procedure with an operating time of between 2 and 5 hours using
either the open or laparoscopic technique. Due to the potential complications of the
surgery and the anaesthetic required, it is primarily offered to younger men in their 60s
who are otherwise healthy, and only rarely offered to men over the age of 75 years.
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Deaths from RP are rare. Thirty-day surgical mortality has been estimated at 0.5%,
although it increases with age and cardiovascular comorbidities (Alibhai 2005).
Complication rates for RP are typically high and include transient urinary incontinence
and erectile dysfunction. Side effects of RP are likely affected by volume of patients per
surgeon, volume of patients per hospital, surgical training and learning curve (Urbanek
2009). Specialised high-volume centres have reported complication rates for long-term
incontinence as low as 2% (Patel et al 2005) and a return to potency among men who
were potent at baseline as high as 97%, with the assistance of phosphodiesterase 5
inhibitors (PDE-5) if required (Menon et al 2005).
The introduction of specialist centres and new techniques such as nerve sparing and
robot-assisted laparoscopic surgery may reduce the generalisability of outcomes from
historical series.
External beam radiotherapy
EBRT, or teletherapy, is the irradiation of the prostate gland from external sources. It is
relatively non-invasive, although it may involve the placement of internal ‘gold seeds’ or
fiducial markers to assist in the accurate localisation of the prostate before and during
treatment.
Over the past 2 decades more accurate and higher dosing techniques have been
developed, such as three-dimensional conformal radiotherapy (3D-CRT) and, more
recently, intensity modulated radiotherapy (IMRT).
EBRT requires a pre-treatment CT scan, which is then loaded onto a specialised computer
that allows a technologist to plan the treatment. Due to the difficulty of accurately
localising the soft tissue of the prostate on CT, MRI scans are often fused with the CT
image to allow more accurate delineation of the prostate. As the prostate is not a fixed
organ, permanent fiducial markers may be inserted to allow it to be ‘tracked’ on a daily
basis while receiving treatment. These improvements in the localisation of the prostate
have enabled increases in overall dose to the target without increasing the dose
to adjacent critical structures. Theoretically, this will improve cancer control without
increasing complications associated with the irradiation of organs such as the bladder,
rectum and bowel.
EBRT may result in urinary and rectal side effects and sexual dysfunction, even with
newer techniques (Zelefsky et al 2006). Unlike surgery, which is more often associated
with incontinence, urinary complications from EBRT tend to be irritative or obstructive
in nature, and include urgency, pain and frequency. These symptoms tend to resolve
within weeks following the completion of radiotherapy, and require only conservative
management. Longer term complications are rare and include urethral stricture (Chrouser
et al 2005), cystitis (Crew et al 2001) and radiation proctitis (Skwarchuk et al 2000).
Like RP, EBRT has changed substantially since its inception. Typical doses in Australia
are currently around 74–78 Gy compared with doses during the two-dimensional
planning era of 64 or 66 Gy. Oncological outcomes and side effect profiles have changed
as well, making historical series difficult to generalise to current practice.
It is difficult to compare studies of EBRT with those of RP because patient groups often
differ substantially. RP is rarely offered to men with locally advanced disease, although
these patients may still be eligible for EBRT. The average age of men receiving EBRT for
prostate cancer tends to be older; and men with multiple comorbidities, who may be
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 15 of 261
refused surgery, may still be eligible for EBRT (Desch et al 1996). Patients are likely to
select a treatment based on its perceived efficacy and on the side effect profiles that each
treatment offers. This may result in men who are particularly averse to particular side
effects choosing treatment with lower likelihoods of those side effects. In the absence of
randomised trials, it is consequently difficult to compare treatments with confidence that
some of the side effect profiles have not been biased by the self-selection of patients for
that particular treatment.
Active surveillance
AS involves forgoing immediate treatment and monitoring for signs of progression or
advancing disease. Australian guidelines do not adequately describe the components or
frequency of AS (Australian Cancer Network Working Party 2002) and the prevalence of
its application in Australia is largely unknown. The increasing incidence of prostate cancer
in countries that have introduced PSA testing has raised interest in AS as a management
option in an attempt to reduce the number of men with indolent or very low risk prostate
cancer being needlessly exposed to the side effects of radical treatment (Klotz 2005). The
intent of AS is to initiate radical treatment once it is apparent that a cancer is no longer
indolent. AS is distinguishable from ‘watchful waiting’ (Hardie et al 2005; Klotz 2005), a
term more commonly used to describe the choice to forgo radical treatment altogether
and introduce conservative treatment if the prostate cancer becomes advanced. It is
therefore inappropriate to classify a man who would be too elderly or infirm, who is
unlikely to benefit from radical intervention, as receiving AS if no treatment is offered.
Despite this, the terms ‘watchful waiting’ and AS continue to be used interchangeably
within the literature, although, for the purposes of this report, they are defined as above.
Due to the lack of standardised AS protocols and triggers for treatment, comparisons of
outcomes from men on AS relative to other treatment options are difficult. A further
complication lies in the lack of studies of men who select or are randomised to AS.
While the comparative effectiveness of AS remains unknown, a recent single-arm study
has reported very promising results, with actuarial 10-year prostate cancer survival of
97.2% among low-risk men (Klotz et al 2010). Similar results from other case series have
prompted international guidelines to encourage clinicians to offer AS to men with lowrisk prostate cancer (National Comprehensive Cancer Network (NCCN) 2010; National
Institute for Health and Clinical Excellence (NICE) 2008) and the initiation of
randomised trials involving AS (Wilt 2008).
Marketing status of the technology
All therapeutic products marketed in Australia require listing on the Australian Register of
Therapeutic Goods (ARTG). LDRBT requires multiple specific instruments including an
applicator and seed-handling equipment, specialist software to allow pre-operative or
intra-operative treatment planning, software that will allow the post-implant verification of
implant adequacy, radiation physics devices to measure the activity of radioactive sources,
and the radioactive seeds themselves. Several companies have BT sources (seeds) listed on
the register.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Current reimbursement arrangements
LDRBT for prostate cancer was first included for reimbursement on the MBS in 2001
and continues to receive interim funding. There are five item numbers associated with the
planning, localisation of the prostate and implantation of radioactive seeds by a urological
surgeon in association with a radiation oncologist at an approved site (items 55603,
15513, 37220, 15338, 15539) (Australian Government Department of Health and Ageing
2010). Table 4 lists the MBS descriptors and reimbursement fees.
Table 4
Medicare Benefits Scheme item numbers and reimbursement for low-dose-rate brachytherapy
for localised prostate cancer
MBS item
Descriptor
Fee
Benefit
(75%)
37220
PROSTATE, radioactive seed implantation of, urological component, using
transrectal ultrasound guidance, for localised prostatic malignancy at clinical
stages T1 (clinically inapparent tumour not palpable or visible by imaging) or T2
(tumour confined within prostate), with a Gleason score of less than or equal to
7 and a prostate specific antigen (PSA) of less than or equal to 10ng/ml at the
time of diagnosis. The procedure must be performed by a urologist at an
approved site in association with a radiation oncologist, and be associated with
a service to which item 55603 applies.
$986.90
$740.20
15338
PROSTATE, radioactive seed implantation of, radiation oncology
component, using transrectal ultrasound guidance, for localised prostatic
malignancy at clinical stages T1 (clinically inapparent tumour not palpable or
visible by imaging) or T2 (tumour confined within prostate), with a Gleason
score of less than or equal to 7 and a prostate specific antigen (PSA) of less
than or equal to 10ng/ml at the time of diagnosis. The procedure must be
performed at an approved site in association with a urologist.
$884.25
$663.20
15513
RADIATION SOURCE LOCALISATION using a simulator or x-ray machine or
CT of a single area, where views in more than 1 plane are required, for
brachytherapy treatment planning for 125I seed implantation of localised
prostate cancer, in association with item 15338
$289.75
$217.35
15539
BRACHYTHERAPY PLANNING, computerised radiation dosimetry for 125I seed
implantation of localised prostate cancer, in association with item 15338
$592.90
$444.70
55603
PROSTATE, bladder base and urethra, transrectal ultrasound scan of.
$109.10
$81.85
Source: Australian Government Department of Health and Ageing (2010) – http://www9.health.gov.au//mbs/search.cfm?pdf=yes –
accessed 2 November 2010
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 17 of 261
Approach to assessment
Objective
To determine whether there is sufficient evidence, in relation to safety, effectiveness and
cost-effectiveness, to recommend public funding for low-dose-rate (LDR) iodine-125
brachytherapy (BT) performed as a monotherapy with curative intent for localised, lowto intermediate-risk prostate cancer.
Clinical pathway
Flowcharts help to define the place of an intervention in the current clinical management
of a disease. The placement of an intervention in a clinical pathway assists with the
identification of the correct comparators, against which safety, effectiveness and costeffectiveness can be measured. The suggested flowcharts provided in Figures 1–3 are
clinical pathways developed in conjunction with, and agreed upon by, the Advisory Panel
for this assessment of LDRBT for the treatment of prostate cancer. The flowcharts have
been amended from those in the 2000 (Medical Services Advisory Committee 2000) and
2005 (Medical Services Advisory Committee 2005) LDRBT reviews to more precisely
reflect the use of additional services and the inclusion of men with Gleason score 7
prostate cancer.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Figure 1
Clinical pathway for men diagnosed with localised prostate cancer with Gleason score = 6
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 19 of 261
See Table 2 for clinical staging and the section on Gleason score on page 7 for explanations; b PSA = prostate specific antigen; c TRUS = transrectal ultrasound; d IPSS = International Prostate Symptom Score; e
TURP = transurethral resection of the prostate; f LHRHa = luteinising hormone-releasing hormone analogue
a
Figure 2
Clinical pathway for men diagnosed with localised prostate cancer with primary Gleason grade = 3 and secondary Gleason grade = 4 (Gleason score = 7)
Page 20 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
a
e
See Table 2 for clinical staging and the section on Gleason score on page 7 for explanations; b PSA = prostate specific antigen; c TRUS = transrectal ultrasound; d IPSS = International Prostate Symptom Score;
TURP = transurethral resection of the prostate; f LHRHa = luteinising hormone-releasing hormone analogue
Figure 3
Clinical pathway for men diagnosed with localised prostate cancer with primary Gleason grade = 4 and secondary Gleason grade = 3 (Gleason score = 7)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 21 of 261
a
e
See Table 2 for clinical staging and the section on Gleason score on page 7 for explanations; b PSA = prostate specific antigen; c TRUS = transrectal ultrasound; d IPSS = International Prostate Symptom Score;
TURP = transurethral resection of the prostate; f LHRHa = luteinising hormone-releasing hormone analogue
Comparator
The aim of this report is to evaluate the evidence of the safety, effectiveness and costeffectiveness of LDR 125I BT in the treatment of localised prostate cancer compared with
radical prostatectomy (RP), external beam radiotherapy (EBRT) and active surveillance
(AS).
Research questions
Safety
For patients with early localised prostate cancer.
1. What is the safety of low-dose-rate 125I brachytherapy, compared with radical
prostatectomy, external beam radiotherapy or active surveillance, in patients with
localised prostate cancer?
Effectiveness
1. What is the effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 6 or less?
2. What is the effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 7 primarily
made up of Gleason grade 3?
3. What is the effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 7 primarily
made up of Gleason grade 4?
Cost-effectiveness
1. What is the cost-effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 6 or less?
2. What is the cost-effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 7 primarily
made up of Gleason grade 3?
3. What is the cost-effectiveness of low-dose-rate 125I brachytherapy, compared with
radical prostatectomy, external beam radiotherapy or active surveillance, in
patients with localised prostate cancer whose total Gleason score is 7 primarily
made up of Gleason grade 4?
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Expert advice
An Advisory Panel with expertise in urology, radiation oncology, radiation physics and
consumer interests was established to provide guidance to the Evaluators to ensure that
the assessment is clinically relevant and takes into account consumer interests. In
selecting members for advisory panels, the MSAC’s practice is to approach the medical
colleges, specialist societies and associations, and consumer bodies for nominees.
Membership of the Advisory Panel associated with this application is provided in
Appendix B.
Review of literature
Literature sources and search strategies
The medical literature was searched to identify relevant studies and reviews for the period
between 2000 and May 2010. The previous MSAC review, performed in 2005, searched
literature from 2000 to 2005; however, given the broadening of the eligibility criteria to
include men with Gleason scores of 7, the Advisory Panel decided to readdress this
period for additional literature regarding men with Gleason 7 prostate cancer. Table 5
describes the electronic databases that were used for this search. Table 6 describes the
strategy used for searching Medline. Similar text words, indexing terms and use of
Boolean operators were employed when searching the other databases. Other sources of
evidence that were investigated are provided in Appendix C.
Table 5
Bibliographic databases
Electronic database
Period covered
CINAHL
2000 – 05/2010
Cochrane Library – including, Cochrane Database of Systematic Reviews, Database of
Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials
(CENTRAL), the Health Technology Assessment Database, the NHS Economic Evaluation
Database
2000 – 05/2010
Current Contents
2000 – 05/2010
Embase.com (including Embase and Medline)
2000 – 05/2010
Pre-Medline
2000 – 05/2010
Web of Science
2000 – 05/2010
EconLit
2000 – 05/2010
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Table 6
Search strategy
Step
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Search text
exp prostate/
exp prostatic diseases/
exp neoplasms/
exp carcinoma/
exp adenocarcinoma/
cancer$.mp.
tumour$.mp.
tumor$.mp.
malignan$.mp.
or/3-9
10 and prostat$.mp.
exp prostatic neoplasms/
1 or 2 or 11 or 12
exp brachytherapy/
brachy-therapy$.mp.
brachytherap$.mp.
(prostat$ adj3 implant$).mp.
(irradiation or radiation or radiotherap$).mp.
seed$.mp.
18 and implant$.mp.
((irradiation or radiation or radiotherap$) adj3 interstitial).mp.
("ldr" or low dose rate).mp.
((iodine or I) adj3 "125").mp.
(iodine adj3 implant$).mp.
or/14-17
or/19-24
25 or 26
13 and 27
Animals/
Humans/
29 not (29 and 30)
28 not 31
limit 32 to yr=2000-2010
Inclusion / exclusion criteria
In general, studies were excluded if they:
 did not address the research question;
 assessed high-dose-rate brachytherapy;
 assessed brachytherapy predominantly using an isotope other than 125I;
 assessed brachytherapy provided in combination with external beam radiotherapy; or
 assessed brachytherapy in a population that would be ineligible for MBS
reimbursement in Australia;
 were in a language other than English and were of a lower level of evidence than
available studies in English;
 did not have the appropriate study design; or
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 did not address, or provided inadequate data on, one of the pre-specified outcomes.
If the same data were duplicated in multiple articles, results from only the most
comprehensive article were included. If articles with duplicate data provided different
analyses relevant to this review, it is made explicit in the reporting that results are based
on overlapping populations.
The inclusion criteria relevant to each of the research questions posed in this assessment
are provide in Box 1, Box 2 and Box 3 in the Results section of this report.
Search results
The process of study selection for this report went through six phases:
1. All reference citations from all literature sources were collated into an Endnote ™ X3
database.
2. Duplicate references were removed.
3. Studies were excluded, on the basis of the citation information, if it was obvious that
they did not meet the pre-specified inclusion criteria. All other studies were retrieved
for full-text assessment.
4. Studies were included to address the research questions if they met the pre-specified
criteria applied by the reviewer on the full-text articles. Those articles meeting the
criteria formed part of the evidence-base.
5. The reference lists of the included articles were pearled for additional relevant studies.
These were retrieved and assessed according to phase 4.
6. The evidence-base consisted of articles from phases 4 and 5 that met the inclusion
criteria.
Any doubt concerning inclusion at phase 4 was resolved by consensus between two
reviewers. The results of the process of study selection are provided in the PRISMA
flowchart at Figure 4.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Figure 4
PRISMA flowchart outlining the process of study selection
Source: Liberati et al (2009)
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Data extraction and analysis
A profile of key characteristics was developed for each included study (Appendix J).
These study profiles describe authors, publication year, location of study, level of
evidence, quality assessment, study design, study population characteristics, type of
intervention, inclusion/exclusion criteria, outcomes assessed and follow-up period.
Comparative studies were available for the safety research questions. Time constraints
limited the extraction of data from case series, and only case series with patient numbers
greater than 250 were extracted. Case series that were found to be eligible but not
extracted are listed in Appendix K.
Studies that were retrieved for full-text review but were found to be ineligible according
to the inclusion criteria are provided in Appendix L.
Appraisal of the evidence
Appraisal of the evidence was conducted in three stages:
Stage 1: Appraisal of the applicability and quality of individual studies included in the
review (strength of the evidence).
Stage 2: Appraisal of the precision, size of effect and clinical importance of the results for
primary outcomes in individual studies—used to determine the safety and
effectiveness of the intervention.
Stage 3: Integration of this evidence for conclusions about the net clinical benefit of the
intervention in the context of Australian clinical practice.
Validity assessment of individual studies
The evidence presented in the selected studies was assessed and classified using the
dimensions of evidence defined by the National Health and Medical Research Council
(NHMRC 2000).
These dimensions (Table 7) consider important aspects of the evidence supporting a
particular intervention and include three main domains—strength of the evidence, size of
the effect and relevance of the evidence. The first domain is derived directly from the
literature identified as informing a particular intervention; the last two each require expert
clinical input as part of its determination.
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Table 7
Evidence dimensions
Type of evidence
Definition
Strength of the evidence
Level
The study design used, as an indicator of the degree to which bias has been eliminated by
design.a
Quality
The methods used by investigators to minimise bias within a study design.
Statistical precision
The p-value or, alternatively, the precision of the estimate of the effect. It reflects the
degree of certainty about the existence of a true effect.
Size of effect
The distance of the study estimate from the ‗null‘ value and the inclusion of only clinically
important effects in the confidence interval.
Relevance of evidence
The usefulness of the evidence in clinical practice, particularly the appropriateness of the
outcome measures used.
a
See Table 8
Strength of the evidence
The three subdomains (level, quality and statistical precision) are collectively a measure of
the strength of the evidence.
Level
The level of evidence reflects the effectiveness of a study design to answer a particular
research question. Effectiveness is based on the probability that the design of the study
has reduced or eliminated the impact of bias on the results. The NHMRC evidence
hierarchy provides a ranking of various study designs (‘levels of evidence’) by the type of
research question being addressed (Table 8).
Table 8
Designations of levels of evidence according to intervention research question
Level
Interventiona
Ib
A systematic review of level II studies
II
A randomised controlled trial
III-1
A pseudorandomised controlled trial
(ie alternate allocation or some other method)
III-2
A comparative study with concurrent controls:
▪ Non-randomised, experimental trial
c
▪ Cohort study
▪ Case-control study
▪ Interrupted time series with a control group
III-3
A comparative study without concurrent controls:
▪ Historical control study
▪ Two or more single-arm studies
d
▪ Interrupted time series without a parallel control group
IV
Case series with either post-test or pre-test/post-test outcomes
Sources: Merlin et al (2009); NHMRC (2009)
a Definitions of these study designs are provided in NHMRC (2000), pp. 7–8, and in the accompanying Glossary.
b A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of level
II evidence.
c This also includes controlled before-and-after (pre-test/post-test) studies, as well as adjusted indirect comparisons (ie using A vs B and B
vs C to determine A vs C, with statistical adjustment for B).
d Comparing single-arm studies (ie case series from two studies).
Note A: Assessment of comparative harms/safety should occur according to the hierarchy presented for each of the research questions,
with the proviso that this assessment occurs within the context of the topic being assessed. Some harms (and other outcomes) are rare and
cannot feasibly be captured within randomised controlled trials, in which case lower levels of evidence may be the only type of evidence
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that is practically achievable; physical harms and psychological harms may need to be addressed by different study designs; harms from
diagnostic testing include the likelihood of false positive and false negative results; harms from screening include the likelihood of false
alarm and false reassurance results.
Note B: When a level of evidence is attributed in the text of a document, it should also be framed according to its corresponding research
question, eg level II intervention evidence; level IV diagnostic evidence; level III-2 prognostic evidence.
Quality
Study quality was assessed for comparative studies using a validated checklist (Downs &
Black 1998) that is able to appraise both randomised and observational studies. An
overall determination of good, moderate or poor quality was allocated to studies based on
reaching a minimum total score from the checklist, as well as reaching a minimum score
for the bias and confounding components of the checklist (Table 9). The final question of
the checklist regarding statistical power was not scored but sample size was considered
during study appraisal. Quality appraisal for economic evaluations was performed using a
checklist created by Drummond & Jefferson (1996). Quality appraisal for case series was
performed using a checklist developed by NHMRC (2000).
Table 9
Quality assessment of studies with Downs and Black
Maximum score
Good
Moderate
Poor
Overall score
Bias and confounding
26
13
≥ 20
≥ 10
16–19
6–9
≤ 15
≤5
Statistical precision
Statistical precision was determined based on narrow confidence intervals and small pvalues, giving an indication as to the probability that the reported effect was real and not
attributable to chance (NHMRC 2000). Studies needed to be appropriately powered to
ensure that a real difference between groups could be detected in the statistical analysis.
Size of effect
For intervention studies of LDRBT and comparators it was important to assess whether
statistically significant differences were also clinically important. The minimum effect size
required for clinical importance was not predetermined and was assessed for each study
after accounting for the likely impact of bias and confounding.
Relevance of evidence
The outcomes being measured in this report were assessed as to whether they were
appropriate and clinically relevant. Inadequately validated (predictive) surrogate measures
of a clinically relevant outcome were avoided (NHMRC 2000). Due to the long natural
history of prostate cancer, and the absence of short-term clinically relevant outcomes, the
surrogate marker of disease progression was assessed as a secondary effectiveness
outcome for this review.
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Assessment of the body of evidence
Appraisal of the body of evidence was conducted along the lines suggested by the
NHMRC in their guidance on clinical practice guideline development (NHMRC 2009).
Five components are considered essential by the NHMRC when judging the body of
evidence:
 the evidence base—which includes the number of studies sorted by their
methodological quality and relevance to patients
 the consistency of the study results—whether the better quality studies had results of a
similar magnitude and in the same direction, ie homogeneous or heterogeneous
findings
 the potential clinical impact—appraisal of the precision, size and clinical importance or
relevance of the primary outcomes used to determine the safety and effectiveness of
the intervention
 the generalisability of the evidence to the target population
 the applicability of the evidence—integration of this evidence for conclusions about
the net clinical benefit of the intervention in the context of Australian clinical practice.
A matrix for assessing the body of evidence for each research question, according to the
components above, was used for this assessment (Table 10). Once the results of the
studies were synthesised, the overall conclusion as derived from the body of evidence was
presented to answer each clinical question—see the Discussion section (page 82).
Table 10
Body of evidence assessment matrix
Component
Evidence-basea
A
B
C
D
Excellent
Good
Satisfactory
Poor
Several level I or II
studies with low risk
of bias
One or two level II
studies with low risk of
bias or a systematic
review / multiple level III
studies with low risk of
bias
Level III studies with
low risk of bias, or level
I or II studies with
moderate risk of bias
All studies consistent
Most studies consistent Some inconsistency
and inconsistency may reflecting genuine
be explained
uncertainty around
clinical question
Evidence is
inconsistent
Very large
Substantial
Moderate
Slight or restricted
Population(s) studied
in body of evidence
are the same as the
target population
Population(s) studied in
body of evidence are
similar to the target
population
Population(s) studied in
body of evidence differ
to target population, but
it is clinically sensible to
apply this evidence to
target populationc
Population(s) studied
in body of evidence
are different to target
population, and it is
hard to judge whether
it is sensible to
generalise to target
population
Consistencyb
Clinical impact
Generalisability
Applicability
Directly applicable to Applicable to Australian Probably applicable to
Australian healthcare healthcare context with Australian healthcare
context
few caveats
context with some
caveats
Level IV studies, or
level I to III studies
with high risk of bias
Not applicable to
Australian healthcare
context
Source: NHMRC (2009)
a Level of evidence determined from the NHMRC evidence hierarchy (Table 8)
b If there is only one study, rank this component as ‗not applicable‘.
c For example, results in adults that are clinically sensible to apply to children OR psychosocial outcomes for one cancer that may be
applicable to patients with another cancer
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Results of assessment
Is it safe?
All treatments for prostate cancer incur some risks to normal urinary, bowel and sexual
function. These side effects may be acute or chronic and may have a considerable impact
on patient quality of life. Quality of life is frequently deemed an effectiveness outcome in
health technology assessments; however, as the aim of treatment for localised prostate
cancer is primarily to prolong the life of commonly asymptomatic men, detriments in
health-related quality of life following prostate cancer treatment almost invariably present
as a consequence of treatment side effects, and hence are considered a function of
treatment safety.
Low-dose-rate brachytherapy (LDRBT) for the treatment of early prostate cancer was
assessed for potential patient harms resulting from the procedure. Inclusion criteria were
developed a priori; however, they have been adjusted to reflect the data available for
review. Specifically, the inclusion criteria for studies separated patients into groups based
on Gleason score. However, the literature reported mixed populations of patients with
both Gleason score 6 (or less) and Gleason score 7, and results were not presented in such
a manner that they could be distinguished as distinct subgroups. For this review,
therefore, these groups have been combined. While Gleason score is likely to be a strong
prognostic marker for oncological and survival outcomes, it is less likely to affect safety
outcomes (Andren et al 2006; Burdick et al 2009; Stark et al 2009). It is possible that
patients with more aggressive cancers are treated more aggressively, and may experience
greater treatment-related adverse effects; however, studies did not segregate groups on
Gleason score for safety outcomes. Box 1 outlines the inclusion criteria for assessment of
the safety of using LDRBT.
All reported rates of side effects are crude unless otherwise indicated.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Box 1
Inclusion criteria for studies assessing the safety of low-dose-rate brachytherapy for the
treatment of localised prostate cancer
Research question
1. Is low-dose-rate brachytherapy (LDRBT) as safe as, or safer than, radical prostatectomy (RP)?
2. Is low-dose-rate brachytherapy (LDRBT) as safe as, or safer than, external beam radiotherapy (EBRT?
3. Is low-dose-rate brachytherapy (LDRBT) as safe as, or safer than, active surveillance (AS) (no initial treatment)?
Characteristics
Criteria
Population
Patients with early localised prostate cancer, defined as clinical stage T1 or T2, Gleason score ≤ 7
and a PSA ≤ 10 ng/mL. At least 85% of patients have met these criteria to be included, or patient
groups were stratified such that the eligible cohort component was available for analysis. Animal or
in-vitro studies were not included.
Intervention
Studies involve LDRBT with iodine125 permanent implants. Studies involving palladium103 were
excluded if more than 50% of the sample receives 103Pd, and patient outcomes were not stratified
by radioactive source. Patients who received combined LDRBT with EBRT were not included in
the analysis, and studies were excluded if data could not be separated.
Comparators
RP, EBRT and AS.
Outcome
Primary – urinary and bowel toxicities (obstructive and irritative urinary symptoms, urinary
incontinence, proctitis, rectal bleeding and rectal complications, urethral stricture), sexual
dysfunction or impotence, pain, secondary malignancies and treatment-related events causing
patient death.
Study design
Randomised or non-randomised controlled trials, cohort studies, case-control studies, registers,
case series or systematic reviews of these study designs. Non-systematic reviews, abstracts,
editorials, case reports, studies of less than 20 patients and laboratory studies were excluded.
Search period
January 2000 – May 2010. Studies reviewed as part of the previous MSAC reviews were excluded
unless new information could be extracted from the study due to the expanded eligibility criteria.
Language
Studies in languages other than English were only translated and included if they represented a
higher level of evidence than was available in the English language evidence-base.
Secondary – infection, pain, extended hospital stays.
Primary safety outcomes
Urinary side effects
The prostate gland is located at the bladder neck and entirely encompasses the first part
of the urethra leaving the bladder. Surgical removal of the prostate gland or irritation of
the gland, urethra or bladder by radiation may have consequences relating to normal
urinary function. Urinary side effects following removal of the prostate (radical
prostatectomy, RP) tends to be in the form of incontinence or dribbling, whereas
radiation (brachytherapy, BT, or external beam radiotherapy, EBRT) tends to result in
irritative symptoms such as dysuria and frequency, and obstructive symptoms due to
oedema or stricture. Urinary function following treatment may have a substantial impact
on overall quality of life and patient satisfaction with treatment. There may be
considerable costs to the patient and the health system in managing severe cases of
urinary side effects.
A total of 14 comparative studies were identified that met the selection criteria for
assessing the urinary-related safety of LDRBT as a treatment for early prostate cancer.
These studies are presented in Table 31 and are listed in order of NHMRC level of
evidence and then quality. One study (Borchers et al 2004) was assessed in the previous
MSAC review and was excluded, leaving 13 comparative studies. One randomised
controlled trial (level II evidence) of moderate quality of 200 patients was identified that
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compared RP with LDRBT (Giberti et al 2009). One moderate-quality large retrospective
cohort study (level III-2 evidence) of 1,362 men compared LDRBT, RP, EBRT and AS
(Smith et al 2010). Two prospective and two retrospective cohort studies (level III-2
evidence) of moderate quality of 960, 872, 841 and 304 men compared LDRBT, RP and
EBRT (Ferrer et al 2008; Frank et al 2007; Guedea et al 2009; Wei et al 2002). The
population included in Ferrer et al (2008), a multicentre cohort study, entirely
encompasses that included in Guedea et al (2009), a single centre study; however, the
analysis by Guedea is performed differently and so both have been considered in this
review. It is made explicit when both studies are being considered. One matched
comparison of two single-arm (level III-3 evidence), one prospective and two
retrospective cohort studies (level III-2) of moderate quality of 278, 104, 374 and 809
men compared LDRBT and EBRT (Eade et al 2008; Pickles et al 2010; Pinkawa et al
2009; Wong et al 2009). Two prospective cohort studies (level III-2 evidence) of
moderate quality of 213 and 435 men (Buron et al 2007; Hashine et al 2008) and one
prospective cohort study (level III-2 evidence) of low quality of 94 men (KirschnerHermanns et al 2008) compared LDRBT and RP. Thirteen case series with study cohorts
of greater than 250 men were also considered in this review. Of all included studies, only
Smith et al (2010) (level III-2 evidence) was undertaken in Australia. KirschnerHermanns et al (2008) compared LDRBT with perineal RP, a surgical technique not
commonly practised in Australia. The study profiles of all included studies are listed in
Appendix J.
Measures of urinary side effects following treatment for prostate cancer are generally
affected by two common symptom groups—urinary incontinence and lower urinary tract
symptoms (LUTS), which are made up of irritative and obstructive symptoms. Side effects
are reported as rates of incontinence, usage of incontinence pads, rates of men
experiencing pain with urination, and frequency of urination; or by using scoring methods
that combine several symptoms into an overall urinary function or urinary bother score.
Comparison between studies that use different scoring tools can be problematic, as can the
interpretation of an overall score given that multiple symptoms may affect its final sum. All
reported rates are crude, unless otherwise specified.
Incontinence
Urinary incontinence (which may also be reported as the need to use pads) can occur
following treatment for prostate cancer, in particular following RP. Incontinence was
evaluated by seven studies of moderate quality and one study of poor quality. The timing
of the assessment varies across the studies from immediately following treatment to 3 or
more years following treatment.
Incontinence was higher following RP than LDRBT at 2 and 6 months (Buron et al
2007), 1 year (Buron et al. 2007), 2 years (Buron et al 2007; Ferrer et al 2008; Guedea et al
2009)4 and 3 or more years (Frank et al 2007; Smith et al 2010) following treatment. In a
randomised controlled trial (Giberti et al 2009), 18.4% of men receiving RP reported
urinary incontinence at 6 months following treatment compared with none in the
LDRBT arm.
Six studies compared LDRBT with EBRT in terms of urinary incontinence following
treatment. Four studies did not show a difference between incontinence or pad usage
4
The cohort reported by Ferrer et al (2008) entirely encompasses that studied by Guedea et al (2009).
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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between the groups (Guedea et al 2009; Ferrer et al 2008; Frank et al 2007; Wei et al
2002)5, one study reported a greater usage of pads in men at 1 month following LDRBT
compared with at the end of EBRT, but there was no difference at a time point
approximately 16 months later (Pinkawa et al 2009); and one study reported low levels of
incontinence at 3 years following treatment for both groups, although it did not report on
effect sizes or statistical significance (Smith et al 2010).
The largest study to report on rates of incontinence is a population-based study by Smith
et al (2010) with 1,362 patients eligible for this review. It is a moderate-quality report of
level III-2 evidence and is the only study to involve an AS comparator. Urinary
incontinence (as measured by the need to wear one or more pads per day) following RP at
3 years was reported as 12.3% compared with 5.4%, 2.7% and 3.4% for LDRBT, EBRT
and AS respectively. This study was performed in Australia and has good external
validity albeit with several limitations. Baseline characteristics of patients differed between
the treatment groups, with 84.5%, 77.1%, 65.5% and 44.7% of men who received
LDRBT, RP, AS and EBRT, respectively, reporting that they had private health
insurance; and men who received LDRBT and RP having a comorbidity score of 2 or
more approximately 25% of the time, compared with approximately 40% of men who
received EBRT or AS. Another important source of bias arises from the time at which
men responded to the baseline interview, in which they were asked to recall their
symptoms at 1 month before treatment. The proportion of men who had already started
treatment at the time of the initial interview varied from 88% who received RP to 36%
who received LDRBT.
One comparative study from Germany reported results that conflicted with the other
studies, with no difference in urinary incontinence between the LDRBT group and the
RP group at 1 year. It did, however, report significantly lower pad usage (p<0.001) in the
LDRBT group (Kirschner-Hermanns et al 2008). The authors reported incontinence in
52% of LDRBT patients at 1 year, a rate that is far higher than rates reported in any other
study. The study was small, the surgical technique (perineal RP) is uncommonly used in
Australia and the overall study quality is deemed to be poor. The same study did report
that stress incontinence among men who underwent perineal RP remained significantly
higher than the LDRBT group at 1 year (53% versus 18%, p<0.001), and the proportion
of men experiencing stress incontinence was far lower than the proportion experiencing
incontinence, raising questions of how ‘incontinence’ was defined by the authors. Due to
inconsistencies in data and inadequate reporting, this result should be interpreted with
caution.
Two case series involving more than 250 men reported quite different urinary
incontinence rates following LDRBT. One case series (Matzkin et al 2003) of good
quality reported no urinary incontinence following implantation. The second case series,
of low quality (Schafer et al 2008), reported that 16% of men at a median of 51 months
following treatment were using pads for incontinence. Neither study reported on baseline
continence or pad usage.
One study modelled mean urinary incontinence subscales of the Expanded Prostate
cancer Index Composite (EPIC) questionnaire, adjusting for age, use of hormones, risk
group and baseline scores (Guedea et al 2009). The study reported, in comparison to
5
The cohort reported by Ferrer et al (2008) entirely encompasses that studied by Guedea et al (2009).
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LDRBT, that there was a statistically significant greater reduction (worsening) in mean
urinary incontinence score at 2 years in men treated with RP. On the EPIC incontinence
100-point scale, relative to LDRBT patients, RP patients reported a mean decrease
(worsening) in score of 11.45 points. While this is difficult to translate into rates of urinary
incontinence, an 11-point difference on the questionnaire, adjusting for baseline scores, is
very likely a clinically meaningful difference (Cella et al 2002; Osoba et al 2005). There
was no difference between mean change from baseline for EBRT and LDRBT at
2 years after treatment.
Up to 1 year after treatment, reported rates of incontinence or pad usage varied from
68.4% to 13% following RP, 4% following EBRT, and nil to 17% following LDRBT. At
follow-up longer than 1 year after treatment, reported rates were 12.3% to 49% for RP,
2.7% to 4% for EBRT, nil to 19.7% for LDRBT and 3.4% for AS.
Lower urinary tract symptoms
Irritative and obstructive symptoms were presented as a mean patient score using the
EPIC questionnaire; International Prostate Symptom Score (IPSS); or as a proportion of
men reporting urgency, LUTS, nocturia or pain with urination. In all comparative studies
that reported on irritative or obstructive symptoms, LDRBT resulted in increased
symptoms compared with RP at least up to 1 year in one study (Giberti et al 2009), with
four studies reporting a continued difference beyond 1 year (Frank et al 2007; Ferrer et al
2008; Buron et al 2007; Wei et al 2002). Two of these studies reported differences in
mean EPIC questionnaire score between the groups that are likely of little clinical
significance.
Comparing EBRT with LDRBT, irritative or obstructive symptoms were worse following
LDRBT in three studies at 16 months (Pinkawa et al 2009), 2.5 years (Wei et al 2002) and
greater than 3.5 years (Frank et al 2007) following treatment, and no different in two
studies measuring symptoms at 2 years following treatment. One study reporting a
difference (Frank et al 2007) collected data at very different times following LDRBT and
EBRT (median 3.5 years vs 4.7 years); if symptoms continued to improve with time several
years after treatment, the results may be biased by the greater time for recovery in the
EBRT arm. None of the studies that reported a difference between LDRBT and EBRT
adjusted for baseline urinary function.
In the only randomised controlled trial (Giberti et al 2009), irritative and obstructive
symptoms were presented using the IPSS (which is identical to the American Urological
Association Symptom Score, AUASI). The score, ranging from 0 to 35 and with higher
scores describing worse function, contains seven questions requiring a response along a
6-point Likert scale. All the symptoms described by the questionnaire—incomplete
emptying, urinary frequency, intermittency, urgency, weak stream, straining and
nocturia—are irritative or obstructive in origin. The trial found significantly increased
symptoms at both 6 months and 1 year following LDRBT compared with baseline, but
found no such increase in the RP arm. At 5 years there was no significant difference
between IPSS and baseline in either treatment arm.
Guedea et al (2009) adjusted results for age, use of hormones, risk group and baseline
EPIC irritative symptoms score, and reported that men receiving LDRBT worsened, on
average, 4.76 points more than patients who received RP. While this is statistically
significant, its clinical relevance is uncertain. It has been suggested that a clinically
meaningful difference in quality of life scores is 5–10% of the scale breadth (Cella et al
2002; Osoba et al 2005); therefore, 4.76 points falls just below what might be considered
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clinically meaningful on a 0–100-point scale. One major limitation of this study is the use
of mean scores rather than proportions of patients who achieved a clinically meaningful
change from their baseline score. It is therefore largely unknown whether a small number
of patients experienced large changes or a large number of patients experienced small
changes in their irritative or incontinence scores.
One consistent limitation of all but one of the included studies is the lack of a randomised
design. Only two of the studies (Pinkawa et al 2009; Pickles et al 2010) attempted to match
the baseline characteristics of LDRBT patients with the comparator group (EBRT). Both
primarily matched upon known prognostic factors for treatment effectiveness, and one
matched upon the incidence of comorbidities (Pinkawa et al 2009). Guedea et al (2009)
used post-hoc statistical methods to control for multiple patient characteristics, including
baseline urinary symptoms. No study, however, attempted to match patients on baseline
urinary function, and this has been shown to be a strong predictor of function following
treatment (Chen et al 2009). This, above all other sources of bias, introduces substantial
uncertainty when interpreting these results. As it is a commonly held belief that treatments
using radiation incur higher rates of obstructive symptoms, and surgery results in higher
rates of incontinence, men already harbouring these symptoms before treatment may be
less likely to be offered and more likely to decline these treatments. The most reliable
results must therefore be drawn from the randomised controlled trial in which this bias
cannot have occurred.
Urinary retention and urethral stricture
Urinary retention, or catheterisation rate, was reported by two studies of moderate quality.
Giberti et al (2009), a randomised controlled trial, reported urinary retention following
LDRBT in 10% of patients, and did not report retention among RP patients. A matched
analysis of a LDRBT and EBRT cohort (Pickles et al 2010) reported that 15%
of men who received LDRBT required catheterisation compared with none in the EBRT
arm. Of the men who were catheterised, 42% remained catheterised for more than
1 month. This analysis matched patients on known risk factors for prostate cancer
aggressiveness; however, it is not reported whether LDRBT and EBRT patients differed
in pre-treatment urinary function, which would likely affect the urinary outcomes
following treatment. The generalisability of this result to the present day is uncertain if
the low median EBRT dose (68 Gy) of the study is associated with a reduced likelihood
of urinary retention. However, this is deemed unlikely due to the characteristic timing of
urinary retention in men receiving EBRT. Prostatic oedema tends to occur early in the
course of radiotherapy for prostate cancer and may abate by the end of treatment or soon
after, suggesting that it is unrelated to cumulative dose (expert opinion). It is probable
that men who receive LDRBT are more prone to acute urinary retention than men
treated with either RP or EBRT; however, the extent of that effect cannot be ascertained
from these studies.
Seven case series with sample sizes greater than 250 men reported on rates of urinary
retention. These rates were typically around 10% following LDRBT, ranging from as low
as 2% to as high as 15%. The difference in reported rates is probably due to the
differential use of corticosteroids intra-operatively and/or alpha blockers following seed
implantation in each of the studies, as well as how closely bladder emptying is monitored.
A urethral stricture may require surgical intervention, result in urinary obstruction and/or
substantially impair quality of life. One randomised controlled trial of 200 patients (Giberti
et al 2009) reported urethral stricture rates of 2% among LDRBT patients and
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6.5% among RP patients. One cohort study of moderate quality of 374 patients (Eade et
al 2008) reported a urethral stricture rate of 7% (11 strictures) at a median time of
2.3 years following treatment among men receiving LDRBT compared with nil in patients
receiving EBRT. In this latter study, patient baseline characteristics differed slightly
between the groups; however, given that EBRT patients tend to be older, with larger
prostates and higher baseline urinary morbidity, any associated bias is likely to be small or
negative in direction. In both studies the LDRBT procedure is similar to that used in
Australia, using either pre-operative or intra-operative planning. In the randomised
controlled trial a dose delivered to 90% of the planned radiotherapy target (D90)
> 140 Gy was deemed a good-quality implant; however, eight patients (of 158) from the
cohort study were reportedly dosed to 160 Gy, although this was prior to the
implementation of TG43 recommendations.6 The effective dose is the same as 145 Gy,
which was used following the implementation of TG43. The EBRT procedure was
intensity modulated radiotherapy (IMRT) with a prescription dose to the planning
tumour volume (5–6 mm posterior and 8 mm elsewhere beyond the prostate and
proximal seminal vesicles) of 74–78 Gy. IMRT is not practised universally in Australia;
however, current practice with 3D-CRT is likely to prescribe similar doses. One cohort
study of moderate quality (Wong et al 2009) reported rates of treatment for strictures
following 3D-CRT, IMRT and LDRBT of 2%, 2% and 14% respectively. However, the
authors do not state what proportion of men received palladium implants; therefore, if
there is a difference in the risk of stricture formation between the isotopes, it will be
uncertain to what extent this result can be translated to the Australian context.
These rates of urethral stricture formation among LDRBT patients as reported by the
comparative studies differ markedly (2% vs 7% vs 14%). Three case series with sample
sizes greater than 250 men reported on rates of urethral stricture following LDRBT. The
rates were 1.7%, 1% and 0.15%, all three being far lower than the percentage reported by
either Eade et al (2008) or Wong et al (2009).
Questionnaire-rated urinary function and bother, and clinician-rated side effects
Urinary function is recorded by some instruments as an overall score whose sum may
vary according to multiple side effects. These scores provide a method of comparing
urinary side effects between treatments that are likely to result in different types of side
effects. However, they are unable to describe the mix of symptoms that, together, resulted
in the overall score. For instance, if a cohort who receive RP regard their urinary function
as equal to that of a cohort who receive LDRBT, we cannot conclude that each treatment
has equal side effect outcomes, but rather that the questionnaire has rated the
mix of outcomes as having the same impact on global urinary function. This measure may
be difficult to interpret, and indeed difficult for clinicians to advise patients who may be
averse to one particular side effect but perhaps not another. Similar tools that often
accompany measures of urinary function are questionnaires of urinary bother. These
tools represent the impact of detriments in urinary function on everyday living. One final
method of representing urinary side effects is by clinician-rated scales, in which specific
side effects are classified on a scale of severity. As with patient-reported questionnaires
American Association of Physicists in Medicine (AAPM) Task Group 43 (TG43) recommended
standardised methods for the calibration, measurements of source strength and dose calculation formalism
in the calibration. Dose prescriptions of 160 Gy using the Memorial Sloan-Kettering Cancer Centre
(MSKCC) or Northwest Tumor Institute (NWTI) calculation methods are equivalent to prescriptions of
144 Gy using TG43 calculation methods (Bice et al 1998).‘ ’
6
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that sum together urinary side effects, these scales are unable to describe the precise side
effect profile that led to the final grade.
Four studies of moderate quality have reported on questionnaire scales that are not able to
be separated into irritative/obstructive or incontinence scales. Three of the studies
reported on separate function and bother scales, one using the University of California,
Los Angeles Prostate Cancer Index (UCLA-PCI) questionnaire (Hashine et al 2008), and
two using the EPIC questionnaire that was developed from the UCLA-PCI and has
similarities (Smith et al 2010; Frank et al 2007). The final study, which also uses the EPIC
questionnaire, reported on a summary score of the two urinary subscales (function and
bother) (Ferrer et al 2008). All results are transformed to a 100-point scale. Hashine et al
(2008) reported better urinary function for LDRBT compared with RP at 3, 6, 9 and
12 months following treatment; however, LDRBT patients also had significantly better
urinary function at baseline (94.1±13.9 vs 88.9±19.4, p=0.027). As baseline function
strongly predicts function after treatment, this may be an important source of bias.
Urinary bother, measured in the same study, was greater among RP patients than LDRBT
patients at 1 month and 12 months following treatment, although not at 3, 6 or 9 months.
The UCLA-PCI questionnaire used by Hashine was primarily developed for use
following RP and has fewer questions regarding irritative or obstructive symptoms
resulting from radiation treatments. It is possible that the reported functional difference
between the two groups results from the systematic inability of the UCLA-PCI to capture
functional detriments following LDRBT.
The EPIC questionnaire is an extended version of the UCLA-PCI that was created to
capture side effects from all prostate cancer treatments, but does not suffer the same
measurement bias (Wei et al 2000). Frank et al (2007) used the EPIC questionnaire and,
as stated previously, reported worse urinary incontinence among RP than EBRT and
LDRBT patients, and worse irritative symptoms among LDRBT patients than both RP
and EBRT. However, the study of 960 men was unable to show a difference in either
overall urinary function or urinary bother at an average of 3.5, 4 and 4.7 years following
LDRBT, RP and EBRT respectively. The final study (Smith et al 2010) reported that
mean urinary function at 3 years was better for patients who received EBRT and LDRBT
than patients who received nerve-sparing or non-nerve-sparing RP. Adjusting for age,
baseline function, demographics and comorbidity score, all treatments had lower odds of
having better urinary function than age-matched non-prostate-cancer controls at 1 year;
however, only RP (nerve-sparing or non-nerve-sparing) continued to have lower odds (ie
poorer urinary function) up to 3 years following treatment. The adjusted odds of having
less urinary bother than an age-matched non-prostate-cancer cohort was lower for RP
and LDRBT but not statistically significantly lower for EBRT at 1 year. The odds of
having less urinary bother remained less than 1 for RP to 3 years, at which time EBRT
and LDRBT were also lower, although LDRBT was no longer statistically significantly
different from controls.
Three studies presented urinary side effects according to the Radiation Therapy Oncology
Group (RTOG) morbidity grading system. Pickles et al (2010) reported acute grade 3
urinary side effects in 2.9% of LDRBT patients compared with only 0.7% (crude rate) of
EBRT patients. Late urinary side effects (grade(s) unspecified) were more common in the
LDRBT group (p<0.001). Late side effects scores were available for only 59% of the
EBRT group and 83% of the LDRBT group. Reasons for incomplete data were not
reported, and it is possible that the greater loss to follow-up in the EBRT group may have
biased the results, in particular if patients with side effects were less inclined to continue
participation in the study. The generalisability of the study results is uncertain given that
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only 25% of the EBRT group received more than 68 Gy, which would be deemed an
inadequate dose in today’s practice. Eade et al (2008) also reported higher rates of acute
and late urinary side effects in LDRBT patients compared with EBRT patients. Of the
men who received LDRBT, 26.6% and 19.2%, respectively, suffered acute and late
urinary side effects of RTOG grade 2 or greater, compared with 6.9% and 3.5%,
respectively, for men who received EBRT (p<0.001, p<0.001). In contrast to Pickles et al
(2010), the EBRT procedure doses to a similar level as current-day practice. Wong et al
(2009) reported a significantly greater number of late RTOG grade 3 side effects among
men who received LDRBT (18%) compared with those who received either 3D-CRT
(5%) or IMRT (5%). This analysis reported on the maximum grade at any time following
treatment (> 3 months) and therefore the duration of the side effects remains unclear.
Because the proportion of men who received palladium implants is unknown in this
study, there remains some uncertainty regarding its applicability to the Australian context.
One case series of 562 patients (Zelefsky et al 2007b) reported rates of 17% and 3% of
RTOG late grade 2 and late grade 3 urinary side effects, respectively, following LDRBT.
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Bowel side effects
The posterior margin of the prostate gland abuts the rectum and irradiation of this area is
at risk of dosing both the rectum and other bowel segments. Acute gastrointestinal
inflammation from irradiation is common, usually presenting as an increase in bowel
motion frequency throughout treatment and then settling some months following the end
of treatment. Chronic gastrointestinal symptoms, possibly related to the development of
fibrosis, may range from merely a mild change in bowel habit to less common serious
side effects such as fistulation, perforation or bleeding requiring a transfusion. Some side
effects, such as enduring faecal incontinence, are likely to have serious implications for
patient quality of life and may require invasive, unpleasant and/or costly intervention.
Bowel symptoms may also occur following surgery for prostate cancer, in particular if the
surgery results in direct damage to the rectal tissue or innervation.
A total of 16 comparative studies were identified that met the selection criteria for
assessing the bowel-related safety of LDRBT as a treatment for early prostate cancer.
These studies are presented in Table 32 and are listed in order of NHMRC level of
evidence and then quality. One study (Borchers et al 2004) was assessed in the previous
MSAC review and was excluded, leaving 15 comparative studies. One randomised
controlled trial (level II evidence) of moderate quality of 200 patients was identified that
compared RP with LDRBT (Giberti et al 2009). One moderate-quality, large retrospective
cohort study of 1,362 men (level III-2 evidence) compared LDRBT, RP, EBRT and AS
(Smith et al 2010). Five cohort studies (level III-2 evidence) of moderate quality of 1,584,
960, 872, 841 and 304 men compared LDRBT, RP and EBRT (Ferrer et al 2008; Frank et
al 2007; Guedea et al 2009; Litwin et al 2004; Wei et al 2002). The population included in
the study by Guedea et al (2009) is entirely encompassed by that included in the Ferrer et
al (2008) study; however, analyses of Guedea add to the interpretation of bowel
symptoms and so both studies have been included. One matched comparison of two
single study arms (level III-3 evidence) and three cohort studies (level III-2 evidence) of
moderate quality of 278, 104, 374 and 809 men (Pickles et al 2010; Pinkawa et al 2009;
Eade et al 2008; Wong et al 2009) and one poor-quality retrospective cohort (level III-2
evidence) of 202 men (Tsui et al 2005) compared LDRBT with EBRT. Two cohort
studies (level III-2 evidence) of moderate quality of 435 and 213 men (Buron et al 2007;
Hashine et al 2008) and one cohort study (level III-2 evidence) of low quality of 212 men
(Wyler et al 2009) compared LDRBT with RP. Five case series (level IV evidence) of
study cohorts greater than 250 men have also been considered in this review. The study
profiles of all included studies are listed in Appendix J.
Frequency, incontinence, pain and bleeding
Side effects may arise from irritation or damage to the colon, rectum or other bowel
segments, and for simplicity are referred to as bowel side effects or toxicities. Bowel side
effects may be reported as rates of individual symptoms, such as incontinence or painful
bowel motions, or by using scoring methods that combine several symptoms into an
overall function or bother score. Comparison of studies using different scoring tools can
be problematic, as can the interpretation of an overall score given that multiple symptoms
may affect its final sum. All reported rates are crude unless otherwise specified.
Three studies reported rates of bowel problems following treatment for prostate cancer.
Pinkawa et al (2009) reported an increase in men with a moderate or big problem due to
increased frequency of bowel movements at the end of their treatment in patients who
received EBRT and at 1 month following treatment in patients who received LDRBT. At
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a median of 16 months following treatment, LDRBT patients had a statistically lower
proportion of men (2%) reporting moderate or big problems due to bowel frequency
compared with EBRT (12%) patients. Faecal incontinence 2 years following treatment
was reported to be worse than baseline in 2% and 8.9% of men who received RP and
LDRBT respectively (Buron et al 2007). The authors did not provide a definition of
faecal incontinence and therefore it is unclear whether very minor or infrequent incidents
were included. As a result, it is difficult to draw conclusions regarding this outcome.
According to Pinkawa et al (2009), there was no difference in the frequency of men who
received EBRT or LDRBT who reported bloody stools either immediately after treatment
or at a median of 16 months. Bloody stools were reported by 17% and 12% of EBRT and
LDRBT men at a median of 16 months following treatment. It should be noted that 8%
and 12% of men receiving EBRT and LDRBT, respectively, reported bloody stools
before treatment. It therefore appears that the proportion of men
experiencing bloody stools following EBRT increased by 9% whereas it did not change in
the LDRBT group. Pinkawa did not adjust for baseline rates and it is difficult to conclude
whether there may have been a detectable difference had he done so. Conversely, Buron
et al (2007) found that 15.1% of men receiving LDRBT reported more rectal bleeding at
2 years compared with no increase in rectal bleeding in the RP group.
The proportion of men experiencing painful bowel movements increased following
treatment among those who received EBRT and LDRBT (Pinkawa et al 2009). At
1 month following LDRBT, 27% of men experienced painful bowel movements, which
was significantly lower than the 52% of men in the EBRT group (p<0.01). At a median
of 16 months following treatment, the proportion of patients experiencing painful bowel
movements remained significantly lower in the LDRBT group compared with the EBRT
group (p<0.05). This study has some serious limitations. Patient questionnaires were
completed immediately following EBRT but only at 1 month following LDRBT.
Delaying the questionnaire for LDRBT patients has some merit, given that the radiation
dose for LDRBT is delivered slowly. However, no biological justification for the timing
has been given. Also, 19% of patients in the EBRT arm reported painful bowel
movements before treatment compared with 12% of patients in the LDRBT arm. This
difference is not reported as statistically significant. However, as follow-up responses
have not been adjusted for baseline differences, there is likely to be some confounding
introduced into the results.
The final study reporting on the proportion of men experiencing bowel problems was a
large Australian cohort (Smith et al 2010). At 3 years following treatment, 6.3%, 3.5% and
0% of men treated with AS, RP and LDRBT, respectively, reported moderate to severe
bowel problems compared with 14.3% of men treated with EBRT. However, baseline
bowel problems were vastly disparate between the groups, with 10.6% of men who were
treated with EBRT reporting moderate to severe bowel problems. Without adjustment
for baseline symptoms, there remains substantial uncertainty with regard to this finding.
Questionnaire-rated bowel function and bother, and clinician-rated side effects
Bowel function and bother following treatment can either be reported by the patient or
assessed by the clinician. Of the patient-reported tools, multiple symptoms of bowel
function and their effect on quality of life are summed together into overall scores. These
can be represented as a function score and a bother score, often transformed to a scale of
100, or a combined score that encompasses both function and bother. Tools included in
this review are EPIC, UCLA-PCI and the European Organisation for Research and
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Treatment of Cancer Quality of Life Questionnaire – prostate cancer module (EORTC
QLQ-PR25). Clinician-rated side effects are an assessment of the functional side effects
of prostate cancer treatment on the bowel. RTOG morbidity scales report acute and late
bowel side effects based on predefined criteria.
Eight included studies have reported on bowel function, bother or a combined score
from patient symptom questionnaires. All eight compared LDRBT with RP, and in six
studies RP patients reported better function, less bother or both at some time point
following treatment. Importantly, one of the studies that found no difference (Guedea et
al 2009) had an overlapping population with another larger study that showed a
difference (Ferrer et al 2008); however, the methodology regarding how results were
compared differed between the studies. Five studies compared LDRBT with EBRT, with
four of these reporting better bowel function or bother in men receiving LDRBT. The
largest study, involving 1,276 men treated with RP, 209 men treated with LDRBT and 99
men treated with EBRT, reported a difference in both UCLA-PCI scales of bowel
function and bowel bother between the groups (Litwin et al 2004). In multivariate analyses
controlling for time since treatment, PSA, Gleason score, clinical stage and comorbidities,
treatment remained a significant predictor of bowel function and bowel bother. Despite
this, the increase in bowel function of 2.0 and 5.9 points for LDRBT and RP, respectively,
when compared with EBRT is of questionable clinical relevance given that the scale is 1–
100. However, LDRBT and RP patients both reported bowel bother scores that were 7.1
and 9.4 points higher, respectively, than EBRT, when controlled for the above-mentioned
factors. One shortcoming of the analysis is that it included
responses from all follow-up time periods, many of which have small differences between
the groups, and is therefore relatively insensitive to large differences in scores shortly after
treatment. Absolute bowel function scores were substantially different between RP,
LDRBT and EBRT immediately after treatment (within the first 3 months), with UCLAPCI function scores of 75, 68 and 60 (p<0.001). Bowel bother for RP patients was
significantly better than for EBRT and LDRBT patients (p<0.001), and bother for
LDRBT patients was significantly better than for EBRT patients (p<0.05).
In an Australian-based cohort study (Smith et al 2010), unadjusted mean EPIC bowel
function scores at 3 years following treatment were no different between men treated
with LDRBT, EBRT, RP or AS. In contrast, bowel bother scores were significantly lower
(worse) among men receiving EBRT (79.8) than all other treatments (90.0–90.5 for RP,
91.1 for LDRBT and 88.1 for AS). These scores are not adjusted for pre-treatment
function or bother, and are difficult to interpret in light of possible baseline differences.
Moderate or severe bowel symptoms at 3 years following treatment were reported by
14.5% of men who received EBRT, compared with nil, 3.5% and 6.3% of men who
received LDRBT, RP and AS. More men who received EBRT reported moderate or
severe bowel symptoms at baseline than those who received other treatments; therefore,
this statistic is also prone to confounding.
One cohort study reporting on the EPIC bowel summary score (a combination of
function and bother elements) found no statistical difference between the score at
baseline and at 2 years in patients treated with RP, EBRT or LDRBT, both unadjusted
and adjusted for age, risk group, use of ADT and baseline scores (Guedea et al 2009). A
larger study encompassing the cohort of Guedea et al (2009) by Ferrer et al (2008)
considered absolute EPIC score at 2 years rather than the change from baseline. It
reported that RP had significantly greater (better) EPIC bowel scores than EBRT
(p<0.001) and LDRBT had significantly greater EPIC bowel scores than EBRT
(p<0.001), although these were unadjusted for confounders, including baseline bowel
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function scores. The study by Guedea is, therefore, more methodologically accurate. In
contrast to Ferrer et al (2008) and Guedea et al (2009), Wei et al (2002) found that men
who received LDRBT had significantly lower (worse) bowel scores 2.5 years following
treatment than men who received either RP or EBRT (p<0.0005). Wei modelled data
taking into account time from treatment, age and prostate cancer specific predictors of
survival. Baseline EPIC bowel scores, however, were not reported and so confounding
from different baseline levels of bowel function cannot be ruled out. In addition, an
unknown proportion of LDRBT patients were treated with adjuvant EBRT; therefore,
the outcomes due to LDRBT alone may be influenced by those outcomes of dual-therapy
patients.
In no study was bowel function or bother worse following RP compared with LDRBT,
and in only one study was bowel function or bother worse following LDRBT compared
with EBRT. As with all studies using mean scores, it is impossible to know whether a
change in score represents a small global change in quality of life or a very large change
for only a few.
Four studies comparing EBRT with LDRBT reported on clinician-rated bowel side effects
using the RTOG morbidity scoring scheme. Comparing acute bowel side effects, two
studies of moderate quality reported no difference in the incidence of grade 2 or higher
side effects following EBRT or LDRBT. In one study by Wong et al (2009), acute
gastrointestinal side effects were more common among men receiving IMRT or 3D-CRT
than LDRBT (p<0.001). According to Wong, only 8% of men who received LDRBT
experienced acute grade 2 or greater gastrointestinal side effects, compared with 54% of
men who received 3D-CRT and 46% of men who received IMRT.
In one study involving IMRT prescribed to 74–78 Gy (Eade et al 2008), cumulative late
grade 2 (or higher) side effects were significantly higher in the LDRBT group than the
EBRT group at 3 years (7.8% vs 2.4%, p=0.03). This included one patient with grade 3
proctitis in the LDRBT group. Multivariate analysis, adjusting for age, diabetes, previous
TURP, prostate size and initial AUA score, determined that LDRBT patients were three
times more likely to suffer late grade 2 or higher side effects than IMRT patients (p=0.05).
In contrast, Pickles et al (2010) reported an increased prevalence of late grade 3
(or higher) side effects in EBRT patients at 2–5 years following treatment (p=0.018). One
limitation of this study is the low radiation doses prescribed to patients in the EBRT arm
compared with present day, with only 25% receiving doses in excess of 68 Gy. It is
possible that the rates of bowel side effects would increase with current EBRT
prescriptions. The two conflicting studies have measured rates of side effects differently,
with Eade et al (2008) opting to use a cumulative actuarial method and Pickles et al (2010)
reporting on annual prevalence rates following treatment. Using the actuarial method
does not allow for adjustments to be made when a side effect abates, and might be seen as
a potential limiting factor of the analysis. It is possible that more men experienced late side
effects in one group yet the side effects were shorter lived than the comparator, and an
actuarial analysis would still present the former group as having higher toxicity. While
Pickles et al (2010) matched patients from the two groups on common effectiveness
prognostic factors, both studies suffer from a non-randomised design, and it is difficult to
consider either study as methodologically superior.
One study of moderate quality (Wong et al 2009) and one of low quality (Tsui et al 2005)
found no difference in the incidence of late grade 2 or greater bowel side effects between
EBRT and LDRBT patients. Wong et al (2009) reported more frequent late grade 1 side
effects among patients receiving 3D-CRT or IMRT than among patients receiving
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LDRBT; however, grade 1 side effects can be treated conservatively and may not impact
on patient quality of life.
Two case series involving 712 and 562 men reported RTOG late grade 2 or higher side
effects among LDRBT patients in 9.8% and 7.0% of cases respectively.
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Sexual dysfunction
Arising from the pelvic plexus, the autonomic innervation to the corpora cavernosa of
the penis is delivered by the left and right neurovascular bundles. These microscopic
nerves and vessels, first described by Walsh (Walsh & Donker 1982), are close to the
prostate and are partly responsible for achieving normal erectile function. Historically,
surgical removal of the prostate involved a wide resection of the neurovascular bundles,
and post-surgery erectile dysfunction was frequent. Developments in prostate surgery,
first described by Walsh (Walsh et al 1983), have enabled the identification and
preservation of the neurovascular bundles, with some improvements in erectile function
following treatment. Erectile function may also be affected following treatments using
radiation; and, although irradiation of nerves or erectile tissue has been postulated as the
cause, the mechanisms of post-radiation erectile dysfunction remain unclear.
A total of 11 comparative studies were identified that met the inclusion criteria for
assessing the sexually related safety of LDRBT as a treatment for early prostate cancer.
These studies are presented in Table 33 and are listed in order of NHMRC level of
evidence and then quality. One study (Borchers et al 2004) was assessed in the previous
MSAC review and was excluded, leaving 10 comparative studies. One randomised
controlled trial of moderate quality of 200 patients was identified that compared RP with
LDRBT (Giberti et al 2009). One large cohort study of moderate quality of 1,362 patients
compared RP, LDRBT, EBRT and AS (Smith et al 2010). Four cohort studies, all of
moderate quality, of 960, 872, 841 and 304 men compared RP, LDRBT and EBRT
(Ferrer et al 2008; Frank et al 2007; Guedea et al 2009; Wei et al 2002). As stated
previously, Ferrer et al (2008) entirely encompassed the population within the Guedea et
al (2009) single centre study; however, the latter presented a different analysis and so has
been retained in this review. Two cohort studies of moderate quality of 435 and 213 men
compared RP and LDRBT (Buron et al 2007; Hashine et al 2008). One study of matched
single arms (level III-3 evidence) of moderate quality of 104 men (Pinkawa et al 2009),
and one poor-quality retrospective cohort (level III-2 evidence) of 202 men (Tsui et al
2005), compared LDRBT and EBRT. Four case series with study populations greater
than 250 men were also considered in this review. The study profiles of all included
studies are listed in Appendix J.
Erections adequate for intercourse
Erectile function may be reported either as rates of potency among men or by examining
sexual function as reported by patients on specific sexual function questionnaires. Potency
rates are perhaps most easily measured and interpreted; however, they lack insight into
quality of life aspects that will be captured by instruments measuring sexual
bother. Four studies have reported rates of potency, erections adequate for intercourse or
changes in erectile function from baseline. A study on a large Australian cohort of 1,362
men reported on impotence rates (defined as ‘unable to obtain an erection sufficient for
intercourse’) in men treated with RP, EBRT, LDRBT and AS. It found that rates of
impotence differed markedly before treatment, with the highest rates (30.2%) in EBRT
patients and the lowest (15.6%) in nerve-sparing RP patients (Smith et al 2010). The
baseline impotency rate among men opting for LDRBT was 19%, with 27.3% among
those opting for AS and 27.6% of men opting for non-nerve-sparing RP. The mean age
between the groups was also different, perhaps partly explaining the disparity in
impotency rates; however, it is possible that the differences also represent patient
selection of treatments more favourable for sexual function outcomes. At 3 years
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following treatment, rates of impotency had increased across all treatments, to 86.7%
among men receiving non-nerve sparing RP (the highest reported rate) and 36.4% of men
receiving LDRBT (the lowest reported rate). Rates of impotence had substantially
increased for men who opted for AS; however, 14% of men had been treated within the
follow-up period (many with RP) and therefore the mean results would have been
influenced by the side effects experienced by those treated. Importantly, impotency rates
were lower following LDRBT than nerve-sparing RP (36.4% vs 67.9%), which cannot be
biased by disparate baseline rates given that baseline impotency was lower among men
opting for nerve-sparing RP. While a large number of men (primarily those with good
baseline function) reported the use of phosphodiesterase-5 (PDE5) inhibitors, after
adjusting for age, baseline potency and treatment type, the use of PDE5 inhibitors
appeared to have no effect on potency at 3 years.
Two studies compared potency rates following treatment among men receiving LDRBT
and EBRT. Including only men potent at baseline, Pinkawa et al (2009) found no
difference between post-treatment potency rates following LDRBT (67%) and EBRT
(51%). However, the numbers included in this sub-analysis (29 and 31 for LDRBT and
EBRT respectively) are far too small to determine whether the observed difference of
16% between the samples was statistically significant; therefore, the lack of significance
may be due to a type 2 error. Tsui et al (2005) reported that potency rates in men who
were potent before treatment and who did not receive androgen deprivation therapy
(ADT) as part of treatment were higher at 12 months following LDRBT (95.7%) than
EBRT (68.8%). This analysis has some serious limitations. Firstly, ADT was used in
almost one-third of LDRBT patients, and potency rates are entirely unknown for this
group. This may bias the study if, in men for whom potency is a high priority, adjuvant
ADT with LDRBT was less frequently used. In addition, the authors report that the use
of PDE5 inhibitors was encouraged in men who received LDRBT, whereas it was seldom
offered to men following EBRT.
One study compared potency rates among sexually active men receiving RP and LDRBT,
and found that at 6 months following treatment, 88% and 50.8% of men, respectively,
reported poorer erectile function than at baseline (Buron et al 2007). By 18 months
following treatment, 83.3% and 45.8% of men treated with RP and LDRBT, respectively,
continued to report erectile function diminished from baseline. The use of treatment for
impotence was not equal between the groups; however, it was higher among the RP
group than the LDRBT group (32% vs 12.5%) and therefore the results should be
interpreted with caution.
Questionnaire-rated sexual function and bother
Erectile function may be reported using patient answered questionnaires, such as EPIC,
UCLA-PCI, IIEF or EORTC QLQ-PR25. The EPIC and UCLA-PCI questionnaires are
transformed into a scale of 0–100, with higher scores representing better outcomes. Both
the EPIC and UCLA-PCI have a sexual outcome specific component that can be
presented either as function and bother subscales or as a combined score. The IIEF score
exists as a 15-item and an abridged 5-item (commonly termed the sexual health inventory
for men) questionnaire. The EORTC QLQ-PR25 contains a sexual module of six
questions, which is transformed to a scale of 0–100. Higher scores on all questionnaires
require adequate erections for intercourse, and may be a surrogate for erectile function.
However, a good score on any questionnaire also requires some level of sexual activity,
which may be contingent upon variables unrelated to function, such as emotional and
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
mental status, motivation, other treatment-related sequelae and the existence and sexual
function of a partner.
Seven studies reported on patient-answered questionnaires. One randomised controlled
trial of 200 patients (Giberti et al 2009) reported a significant reduction in mean IIEF
score at 6 months following both RP and LDRBT (p=0.02 and 0.03 respectively). At
subsequent time points (1 and 5 years), mean IIEF in both groups was no different from
baseline. The authors report a significantly greater proportion of men regaining erectile
function (defined as an IIEF > 22) in the LDRBT group than the RP group at both
6 months (58% vs 40%) and 1 year (78% vs 68%) following treatment, although it is
unclear whether these figures represent the entire study cohort or only men with good
erectile function before treatment. There was no difference between treatment groups at
5 years following treatment. The quality of reporting by Giberti et al (2009) is poor and it
is unclear whether the entire study population responded to this questionnaire or whether
it was a subgroup analysis. The use of erectile aids is not reported, statistical comparisons
report on change from baseline rather than differences between groups, and losses to
follow-up are not considered in the analysis. This result should therefore be considered
with caution.
A large Australian study of 1,362 men comparing RP, EBRT, LDRBT and AS (Smith et
al 2010) found that mean UCLA-PCI sexual function scores for each group were lower
3 years following treatment compared to baseline. After adjusting for age, baseline sexual
function, comorbidity score and demographic variables, men treated with EBRT, LDRBT
or AS had higher odds of having better sexual function at 3 years following treatment
than an age-matched group of men without prostate cancer, and compared with men
treated with either nerve-sparing or non-nerve-sparing RP. Sexual bother also worsened
across all treatments but was worse among patients receiving RP. This study represents
64% of all men diagnosed with localised prostate cancer in NSW who were aged less than
70 years at diagnosis. A strength of the study is that it represents outcomes of men who
are treated at centres with varied levels of expertise and patient volume. However, eight
urologists with higher than average patient volumes declined to participate in the study. It
is likely that surgical volume and experience is a predictor of post-operative erectile
function (Meuleman & Mulders 2003), and the reported rate of impotence among men
treated with RP in Smith et al (2010) may therefore represent an overestimation.
Of the remaining five studies that reported on sexual questionnaires, four compared RP,
EBRT and LDRBT, and one compared RP and LDRBT. Four of the five studies
involving RP (Ferrer et al 2008; Frank et al 2007; Guedea et al 2009; Hashine et al 2008)
showed better retention of potency following LDRBT than RP; however, the 304
patients studied by Guedea et al (2009) are also included in the Ferrer et al (2008) cohort
of 841 patients. Adjusting for age, baseline scores, risk group and hormonal treatment,
Guedea reported that LDRBT patients retain, on average, 18.74 more points on a 0–100
EPIC sexual summary scale at 2 years following treatment. While Hashine et al (2008) did
not adjust for baseline score, the authors reported significantly better UCLA-PCI sexual
function among men receiving LDRBT at 1, 3, 6 and 12 months following treatment despite
LDRBT patients starting with a lower mean sexual function. Wei et al (2002), the only
study not to show a difference, reported no difference in EPIC sexual score between
LDRBT and RP patients at 2.5 years following treatment, but did not control for, or
report, baseline sexual function. While this result is a prediction from a multivariate
model adjusting for, among other things, use of hormone therapy, it is still worth noting
that more than half of all LDRBT patients received adjuvant or neo-adjuvant hormone
antagonists compared with 28% of RP patients (p<0.01). In addition, an unknown
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proportion of LDRBT men were treated with adjuvant EBRT; therefore, it is uncertain
how generalisable this result is to LDRBT delivered as monotherapy.
Sexual bother was reported to be worse following RP in one study (Hashine et al 2008),
and no different in another (Frank et al 2007), compared with LDRBT. As bother tends
to decline with time, this disparity may be due to differences in the timing of the
assessment of sexual bother. Hashine reported a difference between LDRBT and RP at
12 months, which is far closer to the treatment than the assessment by Frank that
occurred at an average of 3.5 years and 4 years post LDRBT and RP respectively.
In the four studies that compared LDRBT with EBRT, two studies reported that LDRBT
patients had significantly better sexual function or overall sexual score than EBRT
following treatment (Ferrer et al 2008; Frank et al 2007). Neither study reported on
baseline functioning and therefore it is unknown whether erectile function may be
influenced by treatment selection based on patient preference. In a study of 304 patients,
all of whom are included in the study by Ferrer et al (2008), no difference in sexual
functioning at 2 years following treatment could be detected between men who received
EBRT and LDRBT once the scores were adjusted for age, baseline scores, risk group and
use of ADT. In a cohort study involving 872 patients (Wei et al 2002), EPIC sexual score
was significantly lower (worse) at 2.5 years following LDRBT than EBRT. Baseline sexual
function was not reported and so it is unclear whether confounding has affected the
results. Also, as an unknown number of LDRBT patients also received EBRT, the
generalisability of this result to the Australian context is uncertain.
Two case series of 643 and 342 patients reported potency rates following LDRBT among
men who were potent before the procedure. At 1, 2, 3 and 5 years following LDRBT,
potency was reported in 30%, 34%, 86.8% and 73.4% of patients respectively.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
General health-related quality of life
In addition to urinary, bowel and sexual function or bother, researchers are also interested
in the impact of prostate cancer and its treatments on general quality of life. Quality of life
following treatment for prostate cancer is likely to be, at least in the short term, a function
of the side effects of the treatment, and impairments in quality of life can therefore be
viewed legitimately as safety outcomes. Given the difference in the side
effect profiles of prostate cancer treatments, general quality of life measures have the
advantage of drawing together the overall impact of quite disparate side effects into one
meaningful score. While this allows easier comparison of treatments, it lacks the
descriptive benefits of more symptom-specific scores, which may be important to
consumers who have greater aversion to some side effects than others.
A total of 11 comparative studies were identified that met the inclusion criteria for
assessing post-treatment quality of life related to safety of LDRBT as a treatment for early
prostate cancer. These studies are presented in Table 34 and are listed in order of
NHMRC level of evidence and then quality. One study (Borchers et al 2004) was assessed
in the previous MSAC review and was excluded, leaving 10 comparative studies. One
randomised controlled trial (level II evidence) of moderate quality of 200 patients was
identified that compared RP with LDRBT (Giberti et al 2009). One moderate-quality,
large cohort study (level III-2 evidence) of 1,362 patients compared RP, LDRBT, EBRT
and AS (Smith et al 2010). Four cohort studies (level III-2 evidence) of moderate quality
of 90, 841, 304 and 872 men compared RP, LDRBT and EBRT (Ferrer et al 2008;
Guedea et al 2009; Lee et al 2001; Wei et al 2002). The population studied by Guedea et
al (2009) is entirely encompassed by that reported by Ferrer et al (2008). Two moderatequality cohort studies (level III-2 evidence) of 435 and 213 men (Buron et al 2007;
Hashine et al 2008), and two cohort studies of poor quality of 212 and 94 men
(Kirschner-Hermanns et al 2008; Wyler et al 2009) compared RP and LDRBT. The study
profiles of all included studies are listed in Appendix J.
One randomised controlled trial of moderate quality comparing general quality of life
outcomes following RP and LDRBT reported a significant decrease in all components of
the European Organisation for Research and Treatment of Cancer Quality of life
Questionnaire (EORTC QLQ-C30) at 6 months for both treatments, with the exception
of cognitive function, which was significantly reduced in RP patients only. By 1 year
following treatment, only the physical function and emotional function components of
the questionnaires remained significantly lower than baseline, and by 5 years all
components of the EORTC QLQ-C30 were no different from before treatment. Giberti
et al (2009) performed no comparative statistics, and differences in baseline scores make
direct comparisons problematic.
For the nine remaining studies comparing RP and LDRBT, there were mixed results. In
the study by Kirschner-Hermanns et al (2008), men treated with RP reported a higher
emotional functioning component of the EORTC QLQ-C30 at 1 year. However, no data
on baseline functioning were presented. Wei et al (2002) reported a significantly greater
(better) Functional Assessment of Cancer Therapy – prostate module (FACT-P) score
among men treated with RP than those who received LDRBT at 2.5 years; however,
baseline scores were unavailable and confounding cannot be ruled out. Using EORTC
QLQ-C30, Wyler et al (2009) reported no difference between men treated with LDRBT
and RP, with the exception that LDRBT patients reported a higher score for the
cognitive function component at 25–36 months following treatment. Given the lack of
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differences in other quality of life components, and at other time points, this finding is
difficult to interpret. It is possible, due to the very small numbers of questionnaires at this
(and all other) time points, that this represents a type 1 error. Hashine et al (2008) and
Ferrer et al (2008), both using the Short Form–36 (SF-36) health survey, reported
significant differences in almost all the SF-36 components at 1 month, with LDRBT
outperforming RP. By 3 months LDRBT scores were higher than RP scores in only role
function and body pain (Ferrer et al 2008) and role emotional and role physical (Hashine
et al 2008). Differences did not extend beyond 12 months in either study, and at no time
point for any components in either study did RP patients report a higher mean score than
LDRBT patients. Smith et al (2010) adjusted for age, baseline score, comorbidities and
demographic variables, and reported results from the Short Form–12 (SF-12) health
survey at 1 year. No treatment showed a difference in physical component score than
age-matched non-prostate cancer controls, and only RP patients showed lower odds of
having a higher mental component score than age-matched non-prostate cancer controls.
No differences were reported beyond 1 year. Buron et al (2007), using the EORTC QLQC30, reported significantly smaller detriments in scores for LDRBT at the end of treatment
compared with RP, although by 2 months the LDRBT group remained better only for the
role function component of the QLQ-C30. At all later time points (from
6 months through to 2 years), RP patients reported an improvement in global quality of
life score from baseline that was significantly greater than for those men treated with
LDRBT.
Five studies compared general quality of life following treatment with LDRBT and
EBRT. Ferrer et al (2008) reported higher SF-36 scores for bodily pain and physical
function at 6 months for patients treated with LDRBT compared with those receiving
EBRT. No differences in SF-36 extended beyond 6 months. Lee et al (2001) reported no
difference in quality of life beyond 12 months comparing LDRBT and EBRT groups
using the FACT-P questionnaire. However, the authors did report a significantly greater
worsening in FACT-P among LDRBT patients compared with EBRT patients at
1 month. Wei et al (2002), who modelled FACT-P scores adjusting for age, time since
treatment and pre-treatment cancer severity, found that LDRBT performed significantly
worse than EBRT at 2.5 years. In this study pre-treatment health-related quality of life
values were not available; hence, unmeasured baseline differences in FACT-P may
contribute to the modelled differences at 2.5 years. Smith et al (2010) and Guedea et al
(2009) found that, after adjusting for pre-treatment quality of life, there were no
differences in quality of life following either LDRBT or EBRT.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Summary – What is the safety of low-dose-rate brachytherapy, compared with
external beam radiotherapy, radical prostatectomy and active
surveillance, as a treatment for localised prostate cancer?
Urinary side effects
A total of 13 comparative studies reported on the urinary related safety of low-doserate brachytherapy (LDRBT) compared with external beam radiotherapy (EBRT),
radical prostatectomy (RP) and active surveillance (AS).
The incidence of urinary incontinence increases following treatment for prostate
cancer. Urinary incontinence is more common among men treated with RP than
LDRBT (Buron et al 2007; Ferrer et al 2008; Frank et al 2007; Giberti et al 2009;
Guedea et al 2009; Smith et al 2010), a difference that may continue beyond 3 years.
Incontinence was highest immediately following treatment and was reported in up to
68% of men treated with RP, 17% of men treated with LDRBT and 4% of men
treated with EBRT. By 3 years following treatment, Smith et al (2010) reported
incontinence in 12.3%, 5.4%, 2.7% and 3.4% of men treated with RP, LDRBT, EBRT
and AS respectively. At baseline 6% of men managed with AS and 1% of age-matched
non-prostate cancer men reported some urinary incontinence; therefore, some
incontinence may be unrelated to treatment. Immediately following treatment, men
treated with LDRBT may have higher rates of incontinence than men treated with
EBRT (Pinkawa et al 2009); however, this difference did not endure (Ferrer et al 2008;
Frank et al 2007; Guedea et al 2009; Pinkawa et al 2009; Smith et al 2010; Wei et al
2002).
Irritative or obstructive symptoms are more common following LDRBT than RP, with
differences continuing beyond 12 months following treatment. In a randomised
controlled trial, International Prostate Symptom Score (IPSS), a questionnaire specific
for obstructive or irritative symptoms, was reported to be worse than baseline at
6 months and 1 year for men treated with LDRBT; however, no difference was found
in irritative symptoms in men treated with RP. By 5 years, no difference was reported
between the two treatments. Three studies reported worse irritative or obstructive
symptoms following LDRBT compared with EBRT and two studies reported no
difference. Importantly, one of the studies that reported no difference adjusted for
baseline urinary symptoms, whereas those studies reporting a difference did not.
Urethral stricture may occur among men receiving any treatment for prostate cancer,
although it may be more common following RP or LDRBT than EBRT. A
randomised controlled trial reported urethral stricture in 2% of men treated with
LDRBT and 6.5% of men treated with RP (Giberti et al 2009). However, the
proportion of men developing urethral stricture following LDRBT varied among
studies, from 0.15% to 14%. Consequently, it is difficult to draw conclusions
regarding the likelihood of urethral stricture among patients treated with LDRBT in
this review. Two studies reported urethral stricture among men treated with EBRT in
nil and 2% of patients. Overall, among comparative studies, RP and LDRBT patients
experienced urethral stricture more frequently than EBRT patients.
Urinary retention is more common following LDRBT than RP or EBRT. A
randomised controlled trial reported urinary retention in 10% of men treated with
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LDRBT and in nil men treated with RP (Giberti et al 2009). A retrospective cohort
which matched patients on baseline characteristics (although not urinary function),
reported catheterisation in 15% of men treated with LDRBT compared with nil men
treated with EBRT (Pickles et al 2010).
Bowel side effects
A total of 15 comparative studies reported on the bowel-related safety of LDRBT
compared with EBRT, RP and AS.
Bowel problems occur more frequently among men treated with LDRBT or EBRT
than RP. Bowel motion frequency increased following LDRBT and EBRT; however,
by 16 months, fewer men treated with LDRBT reported a moderate or big problem
due to frequency (2%) than men treated with EBRT (12%).
Rectal bleeding and faecal incontinence increased in men treated with LDRBT more
often than in men treated with RP (Buron et al 2007). No difference in bloody stools
was noted between men treated with EBRT and LDRBT; however, different baseline
rates of men reporting bloody stools may have disguised a greater increase in bloody
stools among men treated with EBRT (Pinkawa et al 2009).
Painful bowel movements are more common in men treated with EBRT than
LDRBT, both immediately after treatment and at a median of 16 months following
treatment (Pinkawa et al 2009). Once again, findings were not adjusted for baseline
symptoms and these results may be biased.
One large cohort study reported worse bowel function and bother (as measured by the
UCLA-PCI questionnaire) among EBRT patients than LDRBT patients, and LDRBT
patients reported worse bowel function and bother immediately after treatment than
RP patients. In a multivariate analysis correcting for differences in baseline patient
characteristics and including responses up to 2 years, treatment remained a significant
predictor of both bowel function and bother.
Sexual dysfunction
A total of 10 comparative studies reported on sexual dysfunction following LDRBT
and at least one of EBRT, RP and AS.
Erectile dysfunction is more common following RP than either EBRT or LDRBT.
Men treated with nerve-sparing RP reported the lowest prevalence of erectile
dysfunction7 (15.6%) compared with men treated with LDRBT (19%), AS (27.3%) or
EBRT (30.2%) (Smith et al 2010). Despite the baseline advantage, at 3 years more
men treated with nerve-sparing RP reported impotence (67.9%) than men treated with
LDRBT (36.4%) or AS (54.3%), and was equal to the proportion of men reporting
impotence among men who received EBRT (67.9%). Men treated with non-nervesparing RP had the highest proportion of impotence (86.7%). Adjusting for age,
baseline sexual function, comorbidities and demographic variables, men treated with
both nerve-sparing and non-nerve-sparing RP experienced a far greater reduction in
7
Defined by Smith et al (2010) as ‘unable to obtain an erection sufficient for intercourse’.
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sexual function as measured by the UCLA-PCI questionnaire than men treated with
AS, EBRT and LDRBT.
This finding is almost unanimously supported by studies included in this review. A
randomised controlled trial reports that by 5 years there is no difference in
International Index of Erectile Function (IIEF) score between patients treated with
LDRBT or RP (Giberti et al 2009). However, the quality of reporting in this study is
poor, and it is not clear what proportion of men took part in this questionnaire or
whether it included only men potent at baseline.
In studies comparing LDRBT and EBRT, only those that did not control for baseline
functioning reported differences between the post-treatment sexual function of men
treated with LDRBT and EBRT.
General health-related quality of life
A total of 10 comparative studies reported on health-related quality of life (HRQoL)
following LDRBT and at least one of EBRT, RP and AS.
After adjusting for pre-treatment HRQoL, there were no differences in quality of life
following RP, EBRT or LDRBT by 2 or 3 years following treatment (Guedea et al
2009; Smith et al 2010). Men treated with LDRBT may experience comparatively
better HRQoL than men treated with RP for a short period of up to 3 months (Buron
et al 2007; Ferrer et al 2008; Hashine et al 2008); however, not all studies were
consistent and one study showed improved quality of life for men receiving RP
beyond 6 months (Buron et al 2007).
Due to inconsistencies in studies and the use of different questionnaires, HRQoL is
difficult to assess in this review. Of studies that reported a difference, they tended to
favour LDRBT over RP soon after treatment. Given that RP patients may experience
immediate symptoms, whereas LDRBT patients may not experience symptoms for
some weeks or months following treatment, this finding fits a clinical model.
Differences between LDRBT and EBRT were inconsistent between studies and
cannot be assessed. Long-term HRQoL is not reliably reported and is unlikely to
differ between treatments.
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Is it effective?
The effectiveness of prostate cancer treatments has not been widely addressed in
epidemiological and medical literature. To date, most investigations have been case series,
focusing on one treatment without reference to an appropriate comparator. Such studies
have therefore been limited to efficacy appraisal, not effectiveness, which requires at least
two treatment options to be compared. The effectiveness of a given treatment will largely
depend on a cancer’s aggressiveness and stage of development as indicated by Gleason
score, clinical stage and prostate specific antigen (PSA) level or kinetics. In the case of
radiation therapies, including brachytherapy (BT) and external beam radiotherapy
(EBRT), prescribed radiation dose and percentage of the prostate receiving the target
dose are important factors that will influence patient outcomes. In the case of radical
prostatectomy (RP), surgical technique will play a role. For all treatment modalities,
effectiveness will depend on overall health (including comorbidities), age and other
demographic variables associated with the patient. Studies investigating the effectiveness
of prostate cancer treatments should take into account all these potential confounding
factors; this assessment will consider the included studies’ claims of effectiveness in light
of these considerations.
The effectiveness of low-dose-rate (LDR) BT for the treatment of early prostate cancer
was assessed relative to other treatments commonly used in Australia. Inclusion criteria
for effectiveness were developed a priori but have been slightly adjusted to reflect the data
available. Given that none of the eligible literature meet the requirement for comparative
data with a minimum of 10-year patient health outcomes, this criterion was changed to
allow studies with a minimum of 5-year outcomes to be included. The inclusion criteria
separated patients into groups based on Gleason score ≤ 6, Gleason score 7 with a
primary score of 3 and a secondary score of 4 (3+4), and Gleason score 7 with a primary
score of 4 and a secondary score of 3 (4+3). Given that no included studies on
effectiveness separated results by Gleason score according to these criteria, analysis of
these groups has been combined. While Gleason score is less likely to affect safety
outcomes, it is a strong prognostic marker for oncological and survival outcomes
(Andren et al 2006; Burdick et al 2009; Stark et al 2009). This assessment is therefore
limited by lack of data that differentiates effectiveness outcomes for patients on the basis
of Gleason score. Most of the included studies have separated results by low-,
intermediate- and high-risk prostate cancer. Generally, low- and intermediate-risk
categories have correlated well with eligible patients as defined by our inclusion criteria,
while patient populations falling within high-risk categories have not. For this reason,
high-risk patients have not been considered for assessment.
Box 2 outlines the inclusion criteria for assessing the effectiveness of LDRBT as a
treatment for low-risk prostate cancer. Primary measures of effectiveness considered for
this review were cancer-specific survival, all-cause survival, clinical local and distant
recurrence-free survival. Quality of life, often considered a function of effectiveness, has
been addressed under safety considerations as the aim of treatment of low- or
intermediate-risk prostate cancer is primarily to prolong the life of men who are often
asymptomatic. Hence, detriments in quality of life are invariably linked to side effects
from treatment. Secondary measures of effectiveness considered for this review were
biochemical disease-free (bNED) survival, progression-free survival confirmed by bone
scan, time to secondary therapy (including hormone therapy), length of hospital stay and
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duration of treatment. Studies eligible for inclusion presented results on secondary
effectiveness only in the form of bNED.
Box 2
Inclusion criteria for studies assessing the effectiveness of low-dose-rate brachytherapy for
the treatment of localised prostate cancer
Research question
1. Is low-dose-rate brachytherapy (LDRBT) as effective as, or more effective than, radical prostatectomy (RP)?
2. Is low-dose-rate brachytherapy (LDRBT) as effective as, or more effective than, external beam radiotherapy
(EBRT)?
3. Is low-dose-rate brachytherapy (LDRBT) as effective as, or more effective than, active surveillance (AS)?
Characteristics
Criteria
Population
Patients with early localised prostate cancer, defined as clinical stage T1 or T2, Gleason score ≤ 7
and a PSA ≤ 10 ng/mL. At least 85% of patients have met these criteria to be included, or patient
groups have been stratified such that the eligible cohort component was available for analysis.
Animal or in-vitro studies were not included.
Intervention
Studies involved LDRBT with iodine125 permanent implants. Studies involving palladium103 were
excluded if more than 50% of the sample received 103Pd, and patient outcomes were not stratified
by radioactive source. Patients who received combined LDRBT with EBRT were not included in
the analysis, and studies were excluded if data could not be separated.
Comparators
RP, EBRT and AS.
Outcome
Primary outcomes:
Cancer-specific survival, all-cause survival, clinical local and distant recurrence-free survival.
Secondary outcomes:
Biochemical disease-free survival (bNED), progression-free survival confirmed by bone scan,
time to secondary therapy and time to hormone therapy. Length of hospital stay, duration of
treatment.
All studies of effectiveness must present, at a minimum, 5-year outcomes.a
Study design
Randomised or non-randomised controlled trials, cohort studies, case-control studies, registers,
or systematic reviews of these study designs. Non-systematic reviews, abstracts, editorials,
case reports and laboratory studies were excluded.
Search period
January 2000 – May 2010. Studies reviewed as part of the previous MSAC reviews were excluded
unless new information could be extracted from the study due to the expanded eligibility criteria.
Language
Studies in languages other than English were only translated and included if they represented a
higher level of evidence than was available in the English language evidence-base.
a Protocol amendment—originally specified 10-year outcomes.
A total of seven comparative studies were identified that met the selection criteria for
assessing the effectiveness of LDRBT as a treatment for early prostate cancer. Of these
studies, one was a randomised controlled trial of moderate quality (Giberti et al 2009).
Five were retrospective cohort studies of moderate quality, of which one (Stokes 2000)
was included in the previous MSAC assessment (1089). No additional information could
be extracted despite the expanded eligibility criteria for this assessment, and therefore the
study by Stokes et al (2000) was excluded. One included study (Vicini et al 2002) was an
indirect comparison of multiple single-arm studies of poor quality. All studies are
presented in Table 35, ranked by NHMRC level of evidence, then quality.
One randomised controlled trial (N=200) compared LDRBT and RP (Giberti et al 2009);
one large population-based study (N=10,179) compared LDRBT, RP, EBRT, androgen
deprivation therapy (ADT) and ‘no treatment’ (Zhou et al 2009); and three studies (Beyer
& Brachman 2000; Pickles et al 2010; Wong et al 2009) (N=2,222, 278 and 853
respectively) compared LDRBT and EBRT. The large inter-institutional study (N=6,877)
by Vicini et al (2009) compared six treatment modalities, but of these only LDRBT,
EBRT, 3D-EBRT and RP were considered eligible (results for neutron therapy and highBrachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 55 of 261
dose-rate BT were excluded from the analysis). No studies were available that compared
LDRBT with AS.
Of the included studies, one presented results for primary effectiveness alone (Zhou et al
2009), two reported primary and secondary effectiveness outcomes (Pickles et al 2010;
Vicini et al 2002), and three reported on secondary effectiveness alone (Beyer &
Brachman 2000; Giberti et al 2009; Wong et al 2009). Specifically, the highest quality
study by Zhou et al (2009) reported prostate cancer specific and all-cause survival at
7 years. Wong et al (2009) and Giberti et al (2009) reported 5-year bNED while Beyer
and Brachman (2009) reported 5-year and 7-year bNED. Pickles et al (2010) reported
number of deaths from prostate cancer, deaths from all other causes and bNED at
5 years, while the poor-quality study by Vicini et al (2002) reported overall survival and
bNED at 5 years.
Primary effectiveness outcomes
The large, population-based study by Zhou et al (2009) was the only study with measures
of effectiveness that included ‘no treatment’8 as a reference. The other comparators were
RP, EBRT and ADT9. Data for a cohort of 10,179 men aged 65 years and older with
incident prostate cancer were obtained from the records of Medicare, a cancer incidence
surveillance system, and death certificates in the US. Of the total study population, 8,255
were diagnosed with localised disease and the remaining patients had distant metastases or
cancer of unknown stage. Only results for patients with localised disease were considered
for this review, as patients in higher risk groups did not satisfy the eligibility criteria and
conclusions specific to low-risk prostate cancer treatment are not possible within
population groups of unknown stage. The study methods allowed for treatment
modalities administered as monotherapy or in combination, but only outcomes of
monotherapy are included in this analysis.
Overall survival at 7 years for the localised disease group was estimated using KaplanMeier methods, and hazard ratios were calculated using Cox regression. The KaplanMeier analysis provided estimates of overall 7-year survival to be 89%, 81% and 71.7%
for RP, LDRBT and EBRT respectively. Comparing the treatment modalities with ‘no
treatment’ as the reference and controlling for age, race, tumour stage, Gleason score and
pre-treatment comorbidity, hazard ratios for RP, LDRBT and EBRT were 0.32 (95% CI
[0.25, 0.41]), 0.40 (95% CI [0.32, 0.52]) and 0.63 (95% CI [0.53, 0.75]) respectively.
Compared with ‘no treatment’, this represented a significant difference for each treatment
modality (p<0.0001), indicating that overall survival was 3, 2.5 and 1.6 times more likely
for RP, LDRBT and EBRT patients respectively. Zhou et al (2009) did not directly
compare LDRBT with the other treatments, but the confidence intervals for LDRBT and
EBRT did not overlap, which suggests a significantly lower likelihood of dying from any
cause among LDRBT patients than EBRT patients. Conversely, the confidence intervals
Zhou et al (2009) indicated that the majority of patients in the ‘no treatment’ group were aged 75 years
and older. It is likely that a large proportion of these patients were contraindicated for treatment, while
some may have been AS patients. It is unlikely that the group as a whole constitutes an AS cohort. For this
assessment, ‘no treatment’ is not considered as a comparator.
9 For the purposes of this assessment, receiving ADT did not provide a basis for patient exclusion, but
ADT monotherapy was not defined as an appropriate stand-alone comparator. Results for ADT, which
Zhou and colleagues compared with the other treatment modalities, are therefore not considered.
8
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
for LDRBT and RP did overlap, suggesting no significant difference in overall survival
between these two treatment options.
Prostate cancer specific survival (Kaplan-Meier) at 7 years was 97.9%, 96.6% and 94.2%
for RP, LDRBT and EBRT respectively. Cox regression analysis, using ‘no treatment’ as
the reference and adjustment for confounders, gave hazard ratios of 0.25 (95% CI [0.13,
0.48]) for RP, 0.45 (95% CI [0.23, 0.87]) for LDRBT and 0.66 (95% CI [0.41, 1.04]) for
EBRT. There was a significant difference observed between the ‘no treatment’ and RP
groups (p<0.0001), indicating that prostate cancer specific survival was four times more
likely among the RP group than among patients who were not treated at all. The
difference between the ‘no treatment’ and LDRBT groups was also significant (p=0.018),
with survival slightly more than two times better among LDRBT patients. However, the
confidence intervals suggest the possibility of no difference in prostate cancer survival
among LDRBT patients compared with either RP or EBRT patients. In any event, given
the width of these confidence intervals, the analysis is likely to be underpowered to show
differences in prostate cancer specific survival.
Deaths from prostate cancer and non-prostate cancer causes were reported by Pickles et
al (2010). One prostate cancer death was observed in each of the LDRBT and EBRT
groups. Death from non-prostate cancer causes totalled 4 patients in the LDRBT group
and 18 patients in the EBRT group (p=0.001) according to 8-year projections. With such
small patient numbers, it is not possible to make conclusive judgements about
effectiveness from these data.
Of the included studies on effectiveness, Vicini et al (2002) reported on the second largest
cohort of patients (N=6877). However, the majority of these patients, who were accrued
from seven centres, were ineligible for the purposes of this assessment on the basis of
one or more prognostic criteria (PSA level, Gleason score and clinical stage). Data could
be extracted for 1,698 eligible patients (clinical stage T1c/T2a, Gleason score
≤ 6 and PSA ≤ 10 ng/mL) from five centres that each presented results for patients
treated with one modality. Overall survival for the LDRBT group treated at Centre 1 was
83%, but was not reported for the LDRBT group treated at Centre 2 or the 3D-EBRT
group at Centre 3. For the EBRT and RP groups (Centres 4 and 5), overall survival was
85% and 97% respectively. Vicini et al (2002) is the lowest quality study in this evidencebase because, by comparing single-arm treatment groups between centres, the likelihood
that confounding has been introduced into the analysis is high. Results cannot be adjusted
for ‘centre’, as in most ‘multicentre’ studies, because the same treatment was not
conducted in all centres. Although there was an attempt to stratify by prognostic factors,
the authors acknowledged that confounding could only be addressed in a randomised
controlled trial.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Table 11
Primary effectiveness outcomes comparing LDRBT, RP and EBRT
Study
Zhou et al (2009)
Actuarial overall survival at 7 years (%)
LDRBT
RP
EBRT
p-value
81.0
89.0
71.7
NR
Actuarial disease-specific survival at 7 years (%)
Zhou et al (2009)
LDRBT
RP
EBRT
p-value
96.6
97.9
94.2
NR
LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; RP = radical prostatectomy; NR = not
reported
Secondary effectiveness outcomes
Biochemical disease-free survival (bNED)
The randomised controlled trial by Giberti et al (2009) provided the highest level of
evidence on secondary effectiveness outcomes. Five-year bNED was reported for 174 out
of the 200 recruited low-risk prostate cancer patients; however, no definition of bNED
was provided. A total of 26 patients (11 in the RP group and 15 in the LDRBT group)
were lost to follow-up. Five-year bNED was 91% for RP and 91.7% for LDRBT.
Wong and colleagues (2009), in the highest quality cohort study reporting on secondary
effectiveness outcomes, observed the 5-year bNED for 853 patients undergoing LDRBT
or EBRT in two modalities—3D conformal and intensity modulated radiotherapy
(IMRT). Biochemical failure was defined as an increase in PSA level of > 2 ng/mL above
the nadir with no backdating (Phoenix definition). Data could only be extracted for lowrisk patients who did not receive ADT (n=327). Five-year bNED was 92% for 3DEBRT, 93% for IMRT and 97% for LDRBT, and no significant differences were
observed.
A similar quality study by Beyer and Brachman (2000) compared 5-year and 7-year bNED
for 1,527 EBRT and 695 LDRBT patients with 41.3 and 51.3 months of median followup respectively. Biochemical failure was defined as rising PSA (ASTRO definition),
initiation of hormonal management, or PSA rising to 10 ng/mL or more despite the lack
of three consecutive elevations.10 Data were stratified according to baseline PSA. For the
LDRBT group with PSA in the range 0–4 ng/mL, 5-year and 7-year bNED was 87% and
85%, respectively, while for the EBRT group, it was 90% in both cases. For the LDRBT
group with PSA > 4–10 ng/mL, 5-year and 7 year bNED was 76% and 66%, respectively,
while for the EBRT group, it was 74% and 69% respectively. There were no statistically
significant differences between the treatment groups for either 5-year or 7- year
biochemical disease-free survival.
The moderate-quality retrospective cohort study (N=278) by Pickles et al (2010) used a
matched-pair design in patients treated with LDRBT and EBRT at a single Canadian
institution. Patients in both groups, each comprising 139 patients, all had low- and
intermediate-risk prostate cancer11 and were analysed for 5-year bNED (Phoenix
definition) using Kaplan-Meier methods. The patients in the intermediate-risk group who
Some patients may have been classified as having failed on the basis of clinical evidence of disease.
Low-risk patients were defined as PSA ≤ 10 ng/mL, T stage ≤ 2c and Gleason score < 7. Intermediaterisk patients were treated with LDRBT plus 6 months of ADT (3 months neoadjuvantly and 3 months
concurrently with LDRBT) under the provision that they either had PSA ≤ 15 ng/mL with a Gleason score
of ≤ 6 or Gleason score of 7 and PSA ≤ 10 ng/mL.
10
11
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
had a PSA > 10 ng/mL (but not > 15 ng/mL), were in all other respects eligible for
inclusion and represented only 10% of the study sample. These patients were reported to
have had localised disease (all patients were stage T2 or less), indicating good prognosis
and eligibility for either LDRBT or EBRT. There were no significant differences between
the groups in terms of any prognostic factors or baseline characteristics, with the
exception that patients who received LDRBT were younger (median age 64 years) than
those who received EBRT (median age 71 years). Within the low-risk group, 5-year
bNED was 94% for LDRBT patients and 88% for EBRT patients (p<0.001; log-rank
test). For the intermediate-risk group, 5-year bNED was 100% and 78% for the LDRBT
and EBRT patients respectively (p≤0.016). For low- and intermediate-risk groups overall,
5-year bNED was 95.2% for LDRBT and 84.7% for EBRT patients (p<0.001). Pickles et
al (2010) reported that only 1 biochemical relapse was seen in the LDRBT group beyond 5
years, whereas 14 additional EBRT patients showed relapse for a projected failure rate of
50% at maximum follow-up. The PSA doubling time among those who experienced
biochemical relapse was a median of 6 months in the LDRBT group and 24 months in
the EBRT group (p<0.001).
In the poor-quality study by Vicini et al (2002), bNED was defined for radiotherapy
patients as per ASTRO consensus and for surgical patients as any detectable level of PSA.
Five-year bNED for the LDRBT groups treated at Centre 1 and Centre 2 was 82% and
89% respectively. Five-year bNED was 85% for the 3D-EBRT group (Centre 3), 71% for
the EBRT group (Centre 4) and 97% for the RP group (Centre 5).
Table 12
Secondary effectiveness outcomes comparing LDRBT, RP and EBRT
Study
Freedom from biochemical recurrence at 5 years (%)
LDRBT
RP
EBRT
p-value
Giberti et al (2009)
91.7
91.0
-
NR
Wong et al (2009)
931
97
-
92 /
0.298
0-4
87
-
90
0.472
>4-10
76
-
74
0.762
Low risk
94
-
88
<0.001
Intermediate risk
100
-
78
≤0.016
Overall
Beyer and Brachman (2000)
PSA, ng/mL
Pickles et al (2010)
95.2
-
84.7
<0.001
Vicini et al (2002)
82 / 893
97
71 / 854
NR
Study
Freedom from biochemical recurrence at 7 years (%)
LDRBT
RP
EBRT
p-value
0-4
85
-
90
0.472
>4-10
66
-
69
0.762
Beyer and Brachman (2000)
PSA, ng/mL
the external beam radiotherapy is separated into 3D-CRT / IMRT; 2 p-value is for between-group comparison for both
time-points; 3 centre 1 / centre 2; 4 EBRT / 3D-EBRT
1
LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; RP = radical prostatectomy; IMRT = intensity
modulated radiotherapy; PSA = prostate specific antigen; NR = not reported
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Summary – What is the effectiveness of low-dose-rate brachytherapy, compared
with external beam radiotherapy, radical prostatectomy and active
surveillance, as a treatment for localised prostate cancer?
Primary effectiveness outcomes
A total of three comparative studies reported on primary effectiveness outcomes for
low-dose-rate brachytherapy (LDRBT) (Pickles et al 2010; Vicini et al 2002; Zhou et al
2009).
Overall survival after treatment was assessed in two studies. The highest quality study
(Zhou et al 2009) did not directly compare LDRBT with the other treatment
modalities (external beam radiotherapy (EBRT) and radical prostatectomy (RP)), but
rather indirectly via comparison with a ‘no treatment’ group. Overall survival results
suggest that LDRBT patients are not likely to fare any worse than EBRT patients and
have similar overall survival to RP patients. The other study (Vicini et al 2002) was of
poor quality and presented data on primary effectiveness for three out of four eligible
treatments—RP, LDRBT and EBRT. With no testing for statistical significance and
questionable conclusions on the part of the authors, the point estimates provide
inadequate evidence for either a difference or similarity between the treatments.
One study (Pickles et al 2010) reported on prostate cancer specific death and death
from all causes; however, this represented a small number of deaths among the total
number of patients after a follow-up of less than 10 years. This similarly provides no
conclusive evidence about the superiority of either treatment used (LDRBT or
EBRT).
Secondary effectiveness outcomes
A total of five comparative studies reported on secondary effectiveness outcomes for
LDRBT (Beyer & Brachman 2000; Giberti et al 2009; Pickles et al 2010; Vicini et al
2002; Wong et al 2009). All but one of these presented results for 5-year freedom
from biochemical recurrence (bNED). In addition, Beyer & Brachman (2000) also
presented 7-year bNED.
Studies that presented bNED were all of moderate quality and the majority (Beyer &
Brachman 2000; Giberti et al 2009; Wong et al 2009) found no differences in
outcomes between LDRBT or EBRT (RP was not assessed in these studies).
Pickles et al (2010) found that bNED was 10% greater among LDRBT patients than
among EBRT patients.
The poor-quality study by Vicini et al (2002) was inadequate to affect the weight of
evidence, indicating that there is no difference in bNED for LDRBT or EBRT. This
was the only study to report on bNED for RP.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
What are the economic considerations?
In its assessment of a new service, the MSAC is required to consider not only the safety
and comparative effectiveness of the service but also the comparative cost and costeffectiveness of the service. The purpose of the economic evaluation is to inform the
decision made by the MSAC on the additional costs and additional gains (health or other
socially relevant outcomes) of the proposed service over the comparator when used in the
Australian healthcare context. This is to ensure that society’s ultimately scarce resources
are allocated to those activities from which it will get the most value.
When undertaking economic analysis, initially a systematic review (and/or meta-analysis)
is produced to determine whether there is evidence that the intervention is comparatively
effective (see Effectiveness section page 55). An economic analysis is only undertaken if
there is evidence that the procedure under consideration is as effective as, or more
effective than, the designated comparator(s). Due to the limited comparative evidence, it is
not possible to definitively conclude whether low-dose-rate (LDR) 125I brachytherapy (BT)
for localised prostate cancer is as effective as, or more effective than, radical
prostatectomy (RP), external beam radiotherapy (EBRT) or active surveillance (AS).
Therefore, only a cost analysis of the expenditures associated with the new procedure
relative to the comparative procedures was conducted.
The cost data cover all non-trivial health system resources; indirect costs, also known as
productivity costs, were not considered. All cost data were acquired from 2008–09 (round
13) public and private estimated Australian Refined Diagnosis Related Groups (ARDRG) cost report, July 2010 Medicare Benefits Schedule, Pharmaceutical Benefits
Scheme (effective 1 September 2010) and the August 2010 version of the prostheses list.
The costing exercise conducted is not intended for fee scheduling purposes, and is not a
recommendation for funding at these levels.
Existing literature
Studies addressing the cost-effectiveness of LDR 125I BT for localised prostate cancer
were assessed for inclusion in this report according to the criteria outlined in Box 3.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Box 3
Inclusion criteria for studies assessing the cost-effectiveness of low-dose-rate brachytherapy
for the treatment of localised prostate cancer
Research question
1. What is the cost-effectiveness of low-dose-rate brachytherapy (LDRBT) compared with radical prostatectomy (RP)?
2. What is the cost-effectiveness of low-dose-rate brachytherapy (LDRBT) compared with external beam radiotherapy
(EBRT)?
3. What is the cost-effectiveness of low-dose-rate brachytherapy (LDRBT) compared with active surveillance (AS) (no
initial treatment)?
Characteristics
Criteria
Population
Patients with early localised prostate cancer, defined as clinical stage T1 or T2, Gleason score ≤ 7
and a PSA ≤ 10 ng/mL. At least 85% of patients have met these criteria to be included, or patient
groups were stratified such that the eligible cohort component was available for analysis. Animal or
in-vitro studies were not included.
Intervention
Studies involve LDRBT with iodine125 permanent implants. Studies involving palladium103 were
excluded if more than 50% of the sample receives 103Pd, and patient outcomes were not stratified
by radioactive source. Patients who received combined LDRBT with EBRT were not included in
the analysis, and studies were excluded if data could not be separated.
Comparators
Gleason ≤ 6: RP, EBRT and AS.
Gleason = 7: RP and EBRT.
Outcome
Incremental cost-effectiveness ratio, cost per life year gained, cost per quality adjusted life year
gained, cost.
Study design
Economic trial-based studies, modeling studies and costing studies.
Search period
January 2000 to May 2010. Studies reviewed as part of the previous MSAC reviews were excluded
unless new information coiuld be extracted from the study due to the increased eligibility criteria.
Language
Studies in languages other than English were only translated and included if they represented a
higher level of evidence than was available in the English language evidence-base.
One health technology assessment (HTA) combining the findings of three systematic
reviews, and three comparative studies, were identified that met the inclusion criteria for
assessing the economic considerations of LDRBT as a treatment for early prostate
cancer. These studies are presented in Table 36 and are listed in order of NHMRC level
of evidence and then quality. One review combining data from three systematic reviews
compared the incremental cost-effectiveness ratio of LDRBT, RP, 3D-CRT, IMRT and
AS (Ollendorf et al 2009a). Three studies compared costs incurred in the delivery of
LDRBT with those incurred in the delivery of RP (Buron et al 2007; Ciezki et al 2000;
Kohan et al 2000). The study profiles of all included studies are listed in Appendix J.
Cost comparisons
Three studies of moderate-quality12 presented the costs of LDRBT compared with the
costs of RP. One multicentre study of moderate quality was undertaken in France (Buron
et al 2007), and the remaining two single-centre studies, one of moderate quality (Ciezki
et al 2000) and one of poor quality (Kohan et al 2000), were undertaken in the US. Two
studies reported that, while the structure of costs differed between RP and LDRBT,
mean overall costs were similar. Buron et al (2007) reported that mean hospital costs after
24 months were 7,463 euros for RP and 7,427 euros for LDRBT (adjusted to 2001 costs).
Immediately following treatment, RP was, on average, 687 euros less expensive than
The quality of these studies was assessed using the checklist produced by Downs and Black (1998)—this
was deemed more appropriate than the checklist developed by Drummond and Jefferson (1996), which
contains criteria specific for economic evaluations and is unsuited for simple cost comparison studies.
12
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
LDRBT, with the costs of hospitalisation largely balancing the costs of the BT seeds. Over
the following 2 years, LDRBT incurred fewer hospital costs and approximately the same
outpatient costs. Interestingly, the production losses reported by Buron were markedly
different comparing LDRBT with RP. By 2 years following treatment, mean costs due to
loss of productivity among working patients were 620 euros for LDRBT and
3,678 euros for RP patients. Kohan et al (2000) reported that mean total charges by 1 year
following treatment were US$13,904.60 for RP and US$13,886.00 for LDRBT. In
contrast with Buron et al (2007), Kohan et al (2000) reported that mean post-treatment
charges were higher for LDRBT (US$2,285.20) than for RP (US$1,007.20).
The final study by Ciezki et al (2000) did not consider post-operative costs and concluded
that perioperative LDRBT costs were 1.85 and 2.05 times greater than RP costs for preplanned and intra-operative planned techniques respectively.
While the practice of LDRBT and RP in all three studies appears similar to that in
Australia, the overall costs are unlikely to be transferable to the Australian setting.
Cost–utility analysis
One HTA was identified that compared the cost-effectiveness of LDRBT, RP, EBRT
and AS (Ollendorf et al 2009a). This report compiles evidence from three systematic
reviews addressing the safety, effectiveness and cost-effectiveness of RP and AS
(Ollendorf et al 2009b), LDRBT and proton-beam therapy (Ollendorf et al 2008), and
intensity modulated radiotherapy (IMRT) (Pearson et al 2007). All three systematic
reviews were undertaken by the Institute for Clinical and Economic Review (ICER). The
reviews addressed the benefits and harms of treatments for localised, low-risk prostate
cancer. Low-risk disease was defined as clinical stage T1–T2a, Gleason score ≤ 6 and
PSA < 10 ng/mL. The reviews required only a preponderance of patients who met the
criteria for low-risk disease and hence many included studies would have been excluded in
this review. For LDRBT only one comparative study was included, which has been
identified by the search criteria for this review and included in relevant sections. All other
studies involving LDRBT were case series (with the exception of one randomised
controlled trial comparing 125I and 103Pd isotopes for LDRBT).
Applying the Drummond et al (1996) checklist to the report on the comparative
effectiveness and value of all treatments reveals a high-quality economic evaluation.
However, the quality of systematic reviews on which the rates of side effects were based
was moderate to poor, using the checklist for systematic reviews developed by NHMRC
(NHMRC 2000). While the search strategies and inclusion criteria appear to have been
appropriately developed and applied, no quality assessment appears to have been done,
reported study characteristics are inadequate and sources of bias or confounding in the
results were only briefly addressed. Ostensibly, the purpose of the systematic review was
the creation of an economic model, and greater care with reporting outcomes from case
series might appear gratuitous. It is therefore perhaps unfair to criticise the reviews
regarding their reporting, in particular when the evidence-base was of such poor quality
to begin with.
The modelled economic analysis was performed with a Markov model with transition
probabilities and health state utilities sourced from existing literature. Costs for primary
treatments and for treating side effects were sourced from published studies, interviews
with clinicians and US Medicare current procedural terminology codes, and adjusted to
2007 US dollars. Side effects from treatments were sourced largely from the combined
ICER systematic reviews.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Several important assumptions were made within the model:
 All treatment modalities are equally effective with respect to survival. Patients have
equal likelihood of biochemical recurrence, disease progression and cancer-specific
death regardless of which primary treatment they choose. Treatments will differ with
respect to side effect profiles only.
 No patient receives adjuvant therapy (all patients are treated with one modality only).
 Men under AS will be treated with RP or IMRT following PSA progression, Gleason
upgrading or patient decision. After 5, 10 and 15 years of AS, respectively, 28%, 45%
and 54% of men will have received definitive treatment.
 Following a period of AS there is no detrimental effect on survival in men who receive
primary treatment (the likelihood of disease progression reverts to that of all other
men who have received the treatment).
Transition probabilities, costs and utilities were sampled using probabilistic sensitivity
analysis. The base-case results for incremental quality adjusted life years (QALYs),
incremental costs and incremental cost per QALY for 65-year-old men is presented in
Table 13.
Table 13
Total and incremental quality adjusted life years, total and incremental cost, and incremental
cost-effectiveness ratio (cost/QALY) of active surveillance, low-dose-rate brachytherapy and
intensity modulated radiotherapy compared with radical prostatectomy for the treatment of
localised prostate cancer
Strategy
QALYs
Incremental
QALYs
Cost
Incremental cost
Cost/QALY
AS
8.97
1.15
$30,422
$2,074
$1,803
LDRBT
8.12
0.30
$25,484
-$2,864
N/Aa
IMRT
8.09
0.27
$37,861
$9,513
$35,233
RP
7.82
Reference
$28,348
Reference
Reference
Note: Incremental values are calculated relative to radical prostatectomy.
QALYs = quality adjusted life years; AS = active surveillance; LDRBT = low-dose-rate brachytherapy; IMRT = intensity modulated
radiotherapy; RP = radical prostatectomy
a Strategy is less costly and more effective than reference strategy.
Under the assumption of equal survival among treatments, the differences in QALYs are
entirely due to the side effect profiles and their assigned utilities. In the base-case result,
LDRBT achieved 0.3 more QALYs than RP. As LDRBT is also less expensive than RP, it
represents a cost-saving in this model. IMRT, which also achieves a QALY advantage
over RP, is more expensive than RP. The extra 3.2 months of perfect health achieved by
choosing IMRT over RP would cost an additional US$9,513, or US$35,233 per additional
QALY gained.
The model has some limitations. First, the rates of treatment side effects were estimated
from the three aforementioned systematic reviews, which were largely based on poorquality, non-comparative studies. Second, the small overall differences in QALYs
between the treatments will make even slight differences in treatment effectiveness
important in calculating overall QALYs gained from the treatments. While the
assumption of equivalent survival of the included treatments is necessary because of the
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
lack of comparative and randomised studies, undetected differences in effectiveness will
largely invalidate the model’s results. Third, the QALYs are calculated using broad
categories of treatment-related side effects (ie urinary side effects, gastrointestinal side
effects and sexual dysfunction). Given that treatments may have different side effect
profiles, the side effects that resulted in the overall loss in QALYs will be different
between treatments. It is likely that some patients will be more averse to some side effects
than others, and their quality of life (QoL) will be impacted to a different extent
depending upon the side effect profile. It may be that a man who values his potency
would suffer greater loss of QoL following RP, while a man who is more likely to
experience urinary retention and require frequent catheterisation may prefer to avoid
radiation treatments. Finally, estimated costs are drawn from the US healthcare system
and are likely to be different in Australia. Given how closely the four treatment strategies
are with respect to QoL outcomes, the model will be sensitive to relatively minor
differences in costs.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Financial impact analysis
Likely number of procedures in a typical year
The number of low-dose-rate (LDR) 125I brachytherapy (BT) procedures for the treatment
of localised prostate cancer per year is likely to rise. In the 2007–08 financial year, 968
procedures were undertaken in Australia, as recorded by the Australian Institute of Health
and Welfare (AIHW). At the same time there were 687 claims for Medicare
reimbursement. The disparity of nearly 300 treatments represents the proportion of
procedures that were undertaken within the public hospital system. Assuming a linear
trend using data from the 2005–06 financial year onward, by the end of the 2010 financial
year roughly 1,400 procedures would take place in either the public or private sector, as
shown in Figure 5.
This projection is crude. First, it fails to take into account the trend of diagnoses
occurring in increasingly younger men with earlier stage or lower grade disease who
would be eligible for LDRBT. It also assumes that there will be no great change in
community preference for comparative treatments, in particular active surveillance (AS).
If trends mirror those in the US, LDRBT is likely to become a treatment of choice for
men with low-risk disease (Cooperberg et al 2004). However, the projected number of
procedures will be constrained by the number of radiation oncology departments with the
equipment and training able to offer LDRBT; it is therefore unlikely that numbers will
increase sharply.
Figure 5
Actual and projected numbers of low-dose-rate brachytherapy procedures (item
number 15338) by financial year
Source: Medicare Item Reports (2010) for item number 15338 (in red), available online
(https://www.medicareaustralia.gov.au/statistics/mbs_item.shtml); AIHW procedural cubes for 15338 (in blue), available online
(http://www.aihw.gov.au/hospitals/datacubes/datacube_proc.cfm)
While the use of LDRBT has been estimated at approximately 1,400 procedures per year,
the use of other treatment modalities is more uncertain. Both radical prostatectomy (RP)
and external beam radiotherapy (EBRT) may be used in men with disease that would not
be suitable for treatment with LDRBT; therefore, utilisation numbers from the AIHW will
be imprecise. The use of AS in Australia is also uncertain. In an Australian
Page 66 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
population-based cohort study (Smith et al 2010), 20% of men diagnosed with Gleason 6
prostate cancer were reported to have opted for AS; however, this study was based on
data from 2000–02 and rates of AS may have altered substantially since.
Likely number of eligible patients in a typical year
No reliable Australian source has been found that reports on the likely distribution of
Gleason scores among men diagnosed with localised prostate cancer. However, a
publication characterising the risk profile of prostate cancer across the US using 2004–05
data from the Surveillance, Epidemiology and End Results (SEER) database (Shao et al
2009) reported that approximately 55% of all patients diagnosed with Gleason ≤ 7
disease have Gleason scores of 2–6, and 45% have Gleason scores of 7.
For simplicity, and because more accurate figures are unavailable, 5,000 incident
diagnoses of localised disease with Gleason score ≤ 7 each year in Australia (as previously
estimated in potential utilisation on page 12) are assumed to be eligible for LDRBT. This
number is based on calculations using 2006 data; changes in prostate cancer incidence will
affect costing estimates.
Of these cases, 55% are assumed to be of Gleason score 2–6 and 45% are Gleason score
7. Initially, overall costs will be estimated on the premise that one-third of patients will
select each of the active treatments. In a subsequent analysis involving AS, it will be
assumed that 20% of patients with Gleason ≤ 6 prostate cancer select AS, with the
remaining 80% distributed equally among LDRBT, RP and EBRT. AS will not be costed
for men diagnosed with Gleason 7 prostate cancer, one-third of whom will be assumed to
select each of the active treatments.
It should be noted that this analysis will only reflect the costs of implementing LDRBT,
EBRT, RP and AS in the population of men who are eligible for LDRBT, and will not
reflect the cost of treating all men diagnosed with prostate cancer.
Unit costs
The work-up for each of 125I LDRBT, EBRT, RP and AS is similar, with a few
exceptions. It is assumed that all patients will be seen by a urologist regardless of the final
treatment decision. Patients undergoing treatments involving radiation will also see a
radiation oncologist. Due to the low-risk profile of patients with clinically localised cancer
with PSA ≤ 10 ng/mL and Gleason score ≤ 6, staging with whole-body bone scan and
computerised tomography scan will not be costed. It is likely that, in practice, a
proportion of such low-risk patients will undergo these staging procedures, but this will
vary from practice to practice. For men with Gleason score 7 disease, staging scans will be
costed for all treatments. In addition, all LDRBT patients will undertake a urine flow study
to ensure they are not at high risk for post-implant urinary retention. It has been assumed
that luteinising hormone releasing hormone analogues (LHRHa) will be used only for
treatments involving radiation. Men receiving LDRBT are assumed to receive one 3month course of LHRHa in one-third of cases for prostate volume reduction. Among
men receiving EBRT, LHRHa is not used for cytoreduction, as it is in LDRBT, but has
been shown to confer a survival advantage in men who take it concurrently with treatment
(D’Amico et al 2004). There appears to be no benefit for such adjuvant use of hormones
among men with low-risk disease (Zeliadt et al 2006); LHRHa have therefore been costed
only among men with Gleason 7 disease, and then only for 6 months in one- third of
cases. However, the adjuvant use of LHRHa may be less common among men with
Gleason scores of 3+4=7 than among men with Gleason scores of 4+3=7; and the
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 67 of 261
costing is therefore likely to be an overestimation of the costs involved in treating men
with 3+4=7 disease. The services accessed are presented in Table 14.
Table 14
Services associated with low-dose-rate 125I brachytherapy, external beam radiotherapy, radical
prostatectomy and active surveillance for localised prostate cancer
Low-dose-rate
brachytherapy
External beam
radiotherapy
Radical
prostatectomy
Active
a
surveillance
Initial urologist consult
X
X
X
X
Initial radiation oncologist
consult
X
X
Whole-body radionuclide scan
X
X
X
X
Computerised tomography
scanb
X
X
X
X
Pre-anaesthetic consult
X
Radiotherapy planning
X
Component
b
X
X
c
Hospitalisation
X
Radiotherapy procedure
X
X
X
X
Surgical procedure
d
Pathology
X
Blood transfusion
X
X
Medications
X
X
X
Follow-up urologist consult
X
X
X
X
Follow-up radiation oncologist
consult
X
X
Follow-up PSA test
X
X
X
X
Re-biopsy
X
aA
high proportion of men on active surveillance will progress to treatment; b Medicare data reveals that whole-body bone scan and
computerised tomography (CT) scan were accessed in the same 18-month period as a brachytherapy procedure in more than 60% and
almost 100% of cases respectively. However, the indication for the scans is not certain (whether they were used specifically for prostate
cancer staging). To reflect best practice, whole-body bone scan and CT scan will only be costed for men with Gleason 7 disease (expert
opinion); c Only 16.5% of brachytherapy procedures in the 2007–08 financial year were flagged as same day or overnight procedures;
the remainder are assumed to have taken place as inpatient procedures; d Pathology associated with radical prostatectomy is the
examination of the entire prostate, whereas for active surveillance it represents the examination of subsequent biopsy material.
Hospitalisation will be required for both LDRBT and RP. Therefore, those procedures
undertaken while in a hospital will be reflected in the total average charge per AR-DRG
estimate (with the exception of the cost of the BT seeds). There is no AR-DRG specific
to the LDRBT procedure and the average costs associated with the broad AR-DRG
involving BT admissions will be heavily skewed by the costs of other, more complex
procedures undertaken within that same AR-DRG in the public hospital system. Given
that the brief admission for the LDRBT procedure is likely to be uncomplicated, an ARDRG with a short average length of stay has been sourced from the private sector and
applied to both public and private costings. The rationale for taking the average cost per
separation from the private sector is that the cost does not involve the salaries of
clinicians, which may be substantial in public sector average separation costs. For the
costing of LDRBT, the salaries of public sector clinicians will then be approximated by
using the MBS reimbursement. The AR-DRG chosen to reflect a simple overnight stay is
L08B – Urethral procedures-CC, which has an average length of stay of 1.43 days and an
average cost of separation of $1,577 in the private sector. This decision will render the
overall costs of LDRBT identical between the two sectors, with the only difference being
the source of funding.
Page 68 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
The AR-DRG linked to retropubic RP is M01Z – Major Male Pelvic Procedures, and has
been used for both public and private costings. The cost per separation for AR-DRG
M01Z differs markedly between the public and private sectors. This is primarily due to the
differing accounting methods that produce the cost per separation figure, which in
the private sector does not include professional fees, pathology or pharmaceutical costs.
However, even when incorporating these fees, the private cost per separation remains
substantially less than the public cost per separation. It is unlikely that this difference
resembles a true difference in the overall costs, but rather a mixture of confounding
elements. Cost per separation is largely estimated from modelled data in the private sector
(Australian Government Department of Health and Ageing 2009b), which will result in the
underestimation of costs involved in complex AR-DRG categories. Admissions in public
institutions tend to be more complex in nature and patients may have a greater number of
comorbidities. In addition, out-of-pocket expenses charged to patients for professional
fees and hospital costs in the private sector are also unrecorded. In a recent publication by
the Productivity Commission (Productivity Commission 2010), cost per separation was
estimated by summing the costs incurred in each admission for both
public and private hospitals. For AR-DRG M01Z, the Commission’s experimental cost
estimates for public and private hospitals were almost identical ($15,175 in public vs
$14,996 in private). In light of this, the true cost of RP is more likely to be reflected by
the overall costs incurred in the public sector. However, costs in the private sector have
also been presented because the proportion of costs borne by the MBS and the
state/territory governments differs between public and private hospitals.
It is important to note that the cost of RP is based on the open technique. There are no
data providing an accurate proportion of men who undergo robot-assisted laparoscopic
prostatectomy in Australia, and this procedure was estimated as $4,262 more costly by the
May 2006 MSAC report (Medical Services Advisory Committee 2006). Therefore, the costs
of RP will be underestimated.
EBRT and AS procedures are performed in an outpatient setting and the cost
implications to either the MBS or the Australian Government will not vary significantly
between the public and private sectors.
AS is not universally practised across Australia; however, the Urological Society of
Australian and New Zealand (USANZ) has recently signed up to participate in the
Prospective Validation of Active Surveillance (PRIAS) study, and endorses the use of AS
among men with low-risk, localised prostate cancer. Despite this, there is no Australianbased recommendation regarding disease monitoring while on AS, nor what constitutes a
trigger for active treatment. Therefore, AS protocols must be sourced internationally.
In costing AS as an option for the management of localised prostate cancer, we are
primarily interested in the proportions of men who remain on AS and those who opt for
active treatment. This is highly variable and most men choose to move to active treatment
rather than move following changes in PSA level or Gleason score on repeat biopsy
(Dall’Era et al 2008; van den Bergh et al 2009). However, this decision represents a reallife observation and will be costed over that of the ideal situation in which men remain
on AS until prompted into active treatment as a consequence of changes to their disease
status. Due to the uncertainty surrounding the assumptions made for AS as well
as its reliance upon the costings of LDRBT, RP and EBRT, it will be addressed following
an analysis involving only active treatments. Data sources and assumptions for the
costing are outlined in the AS section.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 69 of 261
Costs associated with treating prostate cancer are presented in Table 15. A summary of
costs, grouped by work-up/ staging, procedure and consumables for patients in the
private sector is presented in Table 16. Table 17 includes the minimum costs of
monitoring a patient following treatment, assuming that no patient suffers disease
recurrence or progression. Individual unit costs, descriptions of the service and rationale
for their inclusion are addressed at length in Table 37 (BT), Table 38 (EBRT), Table 39
(RP) and Table 40 (AS), located in Appendix M.
Page 70 of 261
Brachytherapy for the treatment of prostate cancer- MSAC 1089.1
Table 15
Costs associated with the treatment of localised prostate cancer
Component
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Low-dose-rate brachytherapy (Table 37)
External beam radiotherapy (Table 38)
Radical prostatectomy (Table 39)
Initial urologist consult
$80.85 (MBS item 104)
$80.85 (MBS item 104)
$80.85 (MBS item 104)
Initial radiation oncologist consult
$80.85 (MBS item 104)
$80.85 (MBS item 104)
Whole-body bone scan
$479.80 (MBS item 61421)
$479.80 (MBS item 61421)
$479.80 (MBS item 61421)
$365.03 (MBS items 56507 or 56409)
$365.03 (MBS items 56507 or 56409)
$365.03 (MBS items 56507 or 56409)
Work-up and staging
Computerised tomography
scana
Urine flow study
$26.05 (MBS item 11900)
Pre-anaesthetic consult
$40.60 (MBS item 17610)
$40.60 (MBS item 17610)
Procedure
Planning and simulation
$592.90 (MBS item 15539)
$1,681.70 (MBS items 15550 and 15562)
Procedure
$1,871.15 (MBS items 37220 and 15338)
$7,392.60 (MBS items 15248 and 15263)b
Anaesthesia
$205.70 (MBS items 21973 and 23063)
Additional imaging
$453.07 (MBS items 55603 and 15513 and
60509 or 60506)d
Hospitalisation (private / public)
$1,577 / $1577e
$1,807.14 (MBS items 37210 and 51303)c
$448.80 (MBS items 20845 and 23114)
$2,834.20 (MBS item 15705)2
$8,685 / $13874f
Pathology
$470.00 (MBS item 72838)
Consumables and medications
125I
brachytherapy seeds
Luteinising hormone releasing hormone
analogue
$7,000 (Prostheses list code ON003)
$369.59 (PBS code 8093Y)
$739.17 (PBS code 8093Y)
Cross-matching and blood
$150.43 (MBS items 65099 and 13706 + $329
per unit of blood)g
Gleason 6 patientsh
Total cost (private / public)
$12,297.75
$12,070.20
$11,682.82 / $13,995.45
$13,142.58
$13,654.20
$12,527.65 / $14,840.28
Gleason 7 patients
Total cost (private / public)
Page 71 of 261
Items in italics are costed for patients with Gleason 7 disease only (Advisory Panel);a Based on Medicare data, 56507 and 56409 are used equally often; therefore, an average cost of these two items has been presented; b
Based on a 37fraction/5 field treatment technique with daily verification imaging; c A surgical assistant is present at 100% of procedures and claims one-fifth of the principal surgeon‘s fee; d A transrectal ultrasound is required
for the brachytherapy procedure and, in two-thirds of cases, fluoroscopy is used (either 60509 or 60506); e Based on AR-DRG L08B – Urethral procedures-CC private sector data used—see discussion for rationale (2008–09
Cost Report); f Based on AR-DRG M01Z – Major male pelvic procedures for public and private separations (2008–09 Cost Report); g Assume all radical prostatectomy patients are cross-matched and 5% of patients require 2
units of blood, $329 per unit (Medical Services Advisory Committee 2006); h Gleason score ≤ 6.
Table 16
Costs of treating localised prostate cancer in the private sector—by Gleason score
Gleason score ≤ 6
Low-dose-rate
brachytherapy
Component
Work-up and staging
External beam
radiotherapy
Radical prostatectomy
$228.35
$161.70
$121.45
Procedure
$4,699.82
$11,908.50
$11,410.94
Consumables and medications
$7,369.59
$0.00
$150.43
$12,297.75
$12,070.20
$11,682.82
Low-dose-rate
brachytherapy
External beam
radiotherapy
Total costs
Gleason score 7
Component
Radical prostatectomy
Work-up and staging
$1,073.18
$1,006.53
$966.28
Procedure
$4,699.82
$11,908.50
$11,410.94
Consumables and medications
$7,369.59
$739.17
$150.43
$13,142.58
$13,654.20
$12,527.65
Total costs
Table 17
Cost of follow-up and cumulative costs of treatment for localised prostate cancer in the
private sector—for patients with Gleason score ≤ 6a
Cost per year (instances)
Component
Source
Unit cost
Urologist subsequent visit
MBS item 105
$40.60
$81.20 (2)
$0.00 (0)
GP visit
MBS item 411
$40.40
$0.00 (0)
$40.40 (1)
PSA test
MBS item 66656
$20.30
$40.60 (2)
$20.30 (1)
Cumulative costs per yearb
Treatment
Year 1
Years 1–3
Year 2
Year 3
Year 4+
Year 5
Year 10
Follow-up alonec
-
$121.80
$243.60
$365.40
$486.80
$790.30
Follow-up aloned
-
$118.72
$231.50
$338.64
$437.55
$644.67
Low-dose-rate brachytherapyd
$12,298
$12,416
$12,529
$12,636
$12,735
$12,942
Radiotherapyd
$12,070
$12,189
$12,302
$12,409
$12,508
$12,715
Radical prostatectomyd
$11,683
$11,802
$11,914
$12,021
$12,120
$12,327
For cumulative costs to treat Gleason 7 patients, add $844.83 to the overall cost of brachytherapy and radical prostatectomy and
$1,584.00 to the overall cost of external beam radiotherapy; b The costs associated with follow-up assume that no patient has a
recurrence or requires further treatment. As there is no evidence that any one treatment is more effective than another, the added costs
for further treatment will be incurred equally across all treatments; c undiscounted costs; d discounted costs (at 5% per annum with half
cycle correction)
a
Costs to the Australian Government
The Australian Government is responsible for payment of the rebate on items from the
MBS. As 125I LDRBT is performed in a hospital facility, the rebate would be 75% of the
schedule fee for a private hospital facility. Many of the services leading up to the
provision of LDRBT occur in an outpatient setting, during which time the MBS will
reimburse 85% of the overall cost. The Australian Government is also responsible for the
difference between the cost of pharmaceutical benefit items and the amount borne by the
consumer. The costs associated with LDRBT, EBRT and RP as borne by the MBS, other
government agencies (federal or state/territory), and the patient or their private insurance
fund are outlined in Table 18 for a private hospital and Table 19 a public hospital.
Page 72 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 18
Costs and source of funding for the treatment of one man with localised prostate cancer in a
private setting with 10 years follow-up
Source of funds
Low-dose-rate
brachytherapy
External beam
radiotherapy
Radical prostatectomy
Costs borne by MBSa
Outpatient attendances and procedures
$194.10
$10,259.67
$103.23
$2,401.40
$0.00
$1,804.78
Follow-up
$578.53
$578.53
$578.53
Gleason 7 only
$718.11
$718.11
$718.11
$0.00
$0.00
$0.00
$367.79
$0.00
$0.00
$0.00
$735.57
$0.00
In-hospital procedures
Cost borne by other government agencies
Hospitalisation
PBS / other
Gleason 7 only
Cost borne by patient /
private insurancea
Outpatient attendances and procedures
$34.25
$1,810.53
$18.22
$9,300.21
$0.00
$9,756.59
$66.15
$66.15
$66.15
$126.72
$130.32
$126.72
Gleason ≤ 6
$13,088.05
$12,860.50
$12,473.12
Gleason 7
$13,932.88
$14,444.50
$13,317.95
In-hospital procedures (inc. seeds)
Follow-up
Gleason 7 only
Total costs
Based on MBS reimbursement of 85% of the fee for benefit for out-of-hospital procedures and MBS reimbursement of 75% of the fee
for benefit for in-hospital procedures.
a
Table 19
Costs and source of funding for the treatment of one man with localised prostate cancer in a
public setting with 10 years follow-up
Source of funds
Costs borne by
Low-dose-rate
brachytherapy
External beam
radiotherapy
$194.10
$10,259.67
Radical prostatectomy
MBSa
Outpatient attendances and procedures
In-hospital procedures
$103.23
$2,401.40
$0.00
$0.00
Follow-up
$578.53
$578.53
$578.53
Gleason 7 only
$718.11
$718.11
$718.11
Hospitalisation
$2,298.00
$0.00
$13,874.00
PBS / other
$7,367.79
$0.00
$0.00
$0.00
$735.57
$0.00
$34.25
$1,810.53c
$18.22
Cost borne by other government agencies
Gleason 7 only
Cost borne by patient / private insurancea
Outpatient attendances and procedures
$1.80b
In-hospital procedures (inc. seeds)
$0.00
$0.00
$66.15
$66.15
$66.15
$126.72
$130.32
$126.72
Total Gleason ≤ 6
$13,088.05
$12,860.50
$14,785.75
Total Gleason 7
$13,932.88
$14,444.50
$15,630.58
Follow-up
Gleason 7 only
Total costs
Based on MBS reimbursement of 85% of the fee for benefit for out-of-hospital procedures and MBS reimbursement of 75% of the fee
for benefit for in-hospital procedures; b The cost of in-hospital procedures is based on the MBS reimbursement as well as the private
hospital average cost per separation for AR-DRG L08B; 100% of the MBS fee (proposed to reflect clinicians‘ fees) will be absorbed by
the government and will not be borne by the patient; c While this figure represents 15% of the MBS fee for external beam radiotherapy,
patients in a public setting will not be expected to bear these costs, which will be absorbed by the state/territory government.
a
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 73 of 261
Despite differences in services used, the three curative treatments differ only slightly in
overall cost. The costs borne by the MBS, however, differ substantially, with EBRT
costing between $10,974 and $11,692, compared with all other treatments costing
between $817 (RP in a public setting for Gleason ≤ 6 disease) and $4,028 (LDRBT in a
public or private setting for Gleason 7 disease). This is primarily because EBRT is
performed as an outpatient procedure whereas RP is performed in an inpatient setting
and the cost of BT seeds (the largest single expense of LDRBT) is not reimbursed by the
MBS.
Treating men with Gleason 7 disease increases the cost to the MBS by approximately
$720 per patient, which is more than one-fifth of the total MBS cost for either LDRBT or
RP. This increased cost is across all treatments, and is made up by an increased use of
staging scans (whole-body bone scan and computerised tomography scan). It is important
to note that different practices exist across institutions and between specialists regarding
the use of staging scans among prostate cancer patients. It is likely that a proportion of
men with Gleason ≤ 6 prostate cancer, despite their low risk of adverse findings, will also
receive staging scans, resulting in an increased cost to the MBS.
Cost to the Australian healthcare system
The total cost of LDRBT, EBRT and RP to the Australian healthcare system includes
payments made through the MBS; the costs of hospitalisation, medications and the
radioactive seeds required for LDRBT; payments made by private insurers; and copayments made by patients. As presented in Table 18, the overall cost to the Australian
healthcare system for treatments delivered in the private sector differs marginally among
the three modalities. For patients with Gleason ≤ 6 disease, LDRBT costs approximately
$13,088, EBRT approximately $12,861 and RP approximately $12,473. For patients with
Gleason 7 disease, both LDRBT and RP increase in overall cost by $845 and EBRT
(which has been costed to involve the addition of 6 months of LHRHa for one-third of
patients) increases in overall cost by $1,584. The costs of LDRBT and EBRT are identical
in the public sector, but RP increases in cost to $14,786 for patients with Gleason ≤ 6
disease and $15,631 for patients with Gleason 7 disease. This increase (of $2,313) is likely
an estimation error based on the different cost per separation in the public and private
sectors for the AR-DRG M01Z. As previously mentioned, AR-DRGs from the public
and private sectors are not directly comparable, and it is likely that the private sector ARDRG cost per separation used in this model slightly underestimates the true cost
associated with RP.
The single largest expenditure for LDRBT is the implanted radioactive seeds. In the
public healthcare sector, this cost is borne by some state/territory governments by
arrangement with individual hospitals, which may limit the provision of LDRBT in the
public system.
Costs associated with continued monitoring following treatment will be identical across
treatments and will be in the range $60–120 per year. Costs of follow-up will increase
markedly upon disease recurrence following LDRBT, RP and EBRT and will include
secondary treatments such as salvage radiotherapy or hormone therapy. Therefore, the
costs presented only apply to those men who receive initial treatment and do not
experience disease recurrence or require further treatment.
Page 74 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Total cost for provision of services to the entire population
To cost the provision of LDRBT to the entire eligible population, costs from the private
and public healthcare sectors have been combined, assuming that 70% of all LDRBT
procedures and 75% of all RPs occur in the private sector. These figures are based on the
disparity between the AIHW clearing house figures (all procedures performed in
Australia) and those services that attracted a Medicare benefit (private procedures only).
The proportion of men treated in the public or private sectors will not affect the costs
associated with the provision of EBRT. It is also assumed that 55% of all men treated will
have Gleason ≤ 6 prostate cancer.
All costs have been discounted at 5% per annum using a half-cycle correction.
Two scenarios have been costed. In scenario 1 the annual costs to the MBS, other
governmental agencies (state/territory governments or Pharmaceutical Benefits Scheme
(PBS)), and patient or private insurer have been estimated if one-third of all 5,000 men
considered to be eligible for LDRBT are equally likely to select either LDRBT, EBRT or
RP. The results of scenario 1 are shown in Table 20. This estimate represents the overall
discounted costs to the Australian healthcare system in the absence of AS.
In scenario 2 it is assumed that 20% of men diagnosed with Gleason ≤ 6 disease are
initially managed with AS, with the remainder of patients (ie 80% of men with Gleason
scores of ≤ 6 and all men with Gleason scores of 7) being distributed equally among
LDRBT, EBRT and RP. This estimate represents the overall costs to the Australian
healthcare system of treating men with localised prostate cancer including the best
approximation of AS utilisation in Australia. Due to the more gradual accrual of costs
among men who opt for AS, discounting future costs will reduce the overall cost of the
AS protocol. Discounting will have little effect on the costs associated with immediate
treatment due to the relatively small costs incurred during the follow-up period.
Table 20
Scenario 1: Total costs borne by MBS, other governmental bodies, and patient or private
insurance over a 10-year period based on one-third of all men electing each treatment
LDRBT
EBRT
MBS
$5,828,622
$18,602,239
Other government
$5,262,185
Patient / private
insurer
Total
RP
LDRBT vs EBRT
LDRBT vs RP
EBRT vs RP
$3,930,815
–$12,773,617
$1,897,807
$14,671,424
$551,680
$5,780,833
$4,710,505
–$518,648
–$5,229,153
$11,113,527
$3,225,540
$12,431,393
$7,887,987
–$1,317,866
–$9,205,853
$22,204,334
$22,379,458
$22,143,041
–$175,124
$61,293
$236,417
In scenario 1 (Table 20) it is assumed that one-third of all patients considered to be
eligible for 125I LDRBT opt for the each of the available treatments (excluding AS).
Assuming that 55% of these patients have Gleason ≤ 6 disease, the total cost to the MBS
would be $28.362 million. Other governmental bodies, such as state/territory
governments or the federal government through the PBS, are responsible for
$11.595 million, and patients or private insurers are responsible for $26.770 million. The
overall cost to the Australian healthcare system would be $66.727 million.
In comparative terms, treating one-third of all patients with LDRBT would cost the MBS,
on average, $12.774 million less than treating the same men with EBRT. However, the
overall cost of treating men with LDRBT is only marginally ($175,000) less than treating
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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them with EBRT. Therefore, the cost saving to the MBS is due entirely to redistribution
of costs from the MBS and toward the state/territory governments (in the public sector)
and private insurers or patients (in the private sector).
One cost associated with both LDRBT and EBRT is the use of LHRHa. In men treated
with LDRBT, LHRHa is primarily used to reduce the overall size of the prostate gland,
and it has been assumed to apply in one-third of cases. In men treated with EBRT,
LHRHa is used only among those who are deemed at a higher risk of cancer spread. For
this analysis, one-third of patients with a Gleason score of 7 have been assumed to have
received 6 months of adjuvant LHRHa. The use of LHRHa in both LDRBT and EBRT
varies between practices. Given that the use of LHRHa represents a substantial cost
($1,108.76 per 3-month dose), small variations in utilisation patterns may result in large
overall impacts in cost.
Treating one-third of all eligible patients with LDRBT would cost the MBS approximately
$1.898 million more than if the same patients were treated with RP. The disparity in this
cost to the MBS is largely because public patients in public hospitals are not eligible for a
Medicare benefit for RP. In contrast, if delivered as an outpatient procedure in a public
hospital, LDRBT (like EBRT) may be eligible for a Medicare benefit. However, the
difference in total costs is small, with LDRBT being $61,293 more costly than RP.
Costs to the Australian Government and healthcare system of active surveillance
AS for many (if not most) men represents deferred treatment, with studies reporting
between 26% and 69% of men under AS opting for active treatment within 10 years
(Roemeling et al 2007; Soloway et al 2010; van den Bergh et al 2009). Therefore, the costs
associated with AS are largely dependent upon the costs of the treatments that men
ultimately select.
The cost of treating 20% of men with Gleason ≤ 6 prostate cancer considered to be
eligible for LDRBT with AS is presented in Table 22. To generate the costing, several
assumptions are required:
1. For the base case, it was assumed that 57% of men would opt for active treatment by
10 years (van den Bergh et al 2009). The rate at which men opt for active treatment is
not linear and assuming a linear trend (ie 5.7% per year) would have implications for
overall cost when discounted. More precisely, the transition from AS to active
treatment occurs more rapidly over the first few years and then decreases over time.
Figure 6 shows the actuarial freedom from treatment from four studies involving AS
and one hypothetical actuarial freedom-from-treatment graph based on 50% more men
opting for treatment each year than observed in the van den Bergh et al (2009) study.
These results have been taken from tables from the respective publications when
available, or extracted from the Kaplan-Meier plots directly. While the use of actual
survival data may improve the accuracy of costing, allowing a more rapid transition to
treatment soon after diagnosis, it is not without risk. Sudden changes in failure rates
from year to year most likely represent fluctuations specific to the study and may not
represent the true transition to treatment in the wider population. However, small
fluctuations in transition rates will have only a small impact on overall cost.
2. It is assumed that one-third of men who opt for active treatment are treated with
LDRBT, one-third with EBRT and one-third with RP. In a cohort study by van den
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Bergh et al (2009), roughly half of the men choosing treatment following AS opted
for RP, half chose EBRT and less than 10% chose hormone therapy. The choice of
treatment following a period of AS may be limited by several factors: upgrading on
repeat biopsy or increases in PSA may render a man unsuitable for LDRBT; and
older men who choose active treatment may be unsuitable for surgery. However, for
this costing, it is assumed that men will remain eligible for all three treatments (BT,
EBRT and RP) and that one-third will choose each modality.
3. No man will progress to incurable disease while on AS. While this assumption may be
tenuous, the likelihood of significant disease progression is low if men are monitored
correctly.
4. Men on AS will receive a PSA test and digital rectal examination (requiring a visit to a
urologist or general practitioner) four times per year. In a recent review Klotz (2010)
recommends a PSA test every 3 months for the first 2 years, then every 6 months
thereafter.
5. One confirmatory biopsy will be performed for every man who remains on AS in the
first year after diagnosis and a subsequent biopsy will be costed for every man who
decides on active treatment. While some clinicians have recommended regular
biopsies for men on AS (Klotz et al 2010; Al Otaibi et al 2008), in reality far fewer
men receive regular biopsies and the assumption of two additional biopsies for every
man who progresses to treatment exceeds the observed biopsy rate in some cohorts
(van den Bergh et al 2009).
6. One transrectal ultrasound (TRUS) will be performed every year for men who remain
on AS, although this has not been costed for the first year, during which all men
receive a TRUS guided biopsy.
7. The cost of immediate treatment (including all costs except for follow-up) has not
been discounted. While using a half-cycle correction warrants the discounting of costs
in the first year, treatments are assumed to occur in the first 6 months and therefore
would not attract discounting. Due to the difficulty in disaggregating the costs
associated with AS as well as uncertainty as to when they would be incurred, costs
associated with AS have not been discounted in the first year. This will result in a
minor overestimation of the overall costs ascribed to AS (less than 0.5%).
8. Follow-up costs have been simplified from variable costs following active treatment
(reducing over time) to a constant cost of $121.80 per year. This will have little impact
on the overall cost of treatments.
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Figure 6
Transition to and from active surveillance to treatment over 10 years
Sources: Soloway et al (2010), Eggener et al (2009), van den Bergh et al (2009), van den Bergh et al (2010) (PRIAS study)
PRIAS (Prostate cancer Research International: Active Surveillance) registered at http://www.trialregister.nVtrialreq/admin/rctview.asp?TC=1718
Individual costs incurred while on AS are presented in Table 21. Active treatment is assumed to
occur as per Table 18 and Table 19, with 70% of men receiving LDRBT and
75% receiving RP in a private se tting. It is assumed that 55% of men eligible for LDRBT will have
Gleason 6 disease. For the base case, 20% of men with Gleason 6 prostate cancer will opt for AS.
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Brachytherapy for the treatment of prostate cancer- MSAC 1089.1
Table 21
Costs associated with active surveillance for localised prostate cancer
Component
Active surveillance (see Table 40)
Year 1
Initial urologist consult
$80.85 (MBS item 104)
Initial radiation oncologist consult
$80.85 (MBS item 104)
PSA test (x4)
$81.20 (unit cost $20.30 MBS item 66656)
Re-biopsy
$584.85 (MBS items 37219, 55600 and 72827)
Urologist follow-up (x4)
$162.40 (unit cost $40.60 MBS item 105)
Years 2–10 while on active surveillance
PSA test (x4)
$81.20 (unit cost $20.30 MBS item 66656)
Urologist follow-up (x4)
$162.40 (unit cost $40.60 MBS item 105)
Transrectal ultrasound
$109.10 (MBS item 55600)
On transition to active treatment
Re-biopsy
$584.85 (MBS items 37219, 55600 and 72827)
Active treatment costsa
Low-dose-rate brachytherapy
$12,297.75
External beam radiotherapy
$12,070.20
Radical prostatectomy
$12,260.98
Follow-up costs
Combined costs per yearb
$121.80 (Table 17)
Treatment costs are based on the per patient costs from Table 18 and Table 19 combined, assuming that 70% of men receive LDRBT
and 75% receive RP in the private sector. Discounted follow-up costs ($644.67) have been excluded from the costs of active treatment
and will be costed separately depending upon the length of time a patient is followed; b The cost of follow-up in analyses presented for
active treatments reduces to $60.70 per year from year 4 onwards, but for simplicity it has been assumed to remain fixed at the initial
rate of $121.80 for all patients regardless of time since treatment.
a
Unlike immediate treatment, in which most of the costs are incurred immediately, the
costs associated with AS are deferred. Therefore, while the overall costs of AS may
approach those of active treatment, discounting the costs will markedly alter the overall
cost of the AS option. A discounting rate of 5% per year, using a half-cycle correction,
has been applied for all analyses.
The annual costs of treating 5,000 men with LDRBT, EBRT, RP or AS are presented in
Table 22. This scenario represents the best estimate of the total cost of treating all men
considered to be eligible for LDRBT in 2010, and involves initiating AS for 20% of all
patients with Gleason ≤ 6 prostate cancer, with 57% eventually receiving active treatment
over the 10-year costing period.
Table 22
Scenario 2: Total discounted costs borne by MBS, Australian healthcare system, and patient
or private insurance over a 10-year period for treating 5,000 men, with 20% of Gleason ≤ 6
men opting for active surveillance1
LDRBT
EBRT
RP
AS
Total
MBS
$5,589,800
$16,958,319
$3,900,752
$2,485,521
$28,934,392
Other government
$4,683,345
$551,680
$5,144,942
$579,952
$10,959,918
Patient / private insurer
$10,015,356
$2,995,345
$11,188,257
$1,590,987
$25,789,944
Total
$20,288,501
$20,505,344
$20,233,950
$4,656,460
$65,684,255
The costs of LDRBT are the weighted average costs associated with treating men 70% in private and 30% in public. The costs of RP
are the weighted average costs associated with treating men 75% in private and 25% in public. The costs of EBRT will not change from
the public and private systems. The costs of all treatments, including AS, are discounted at 5% per year with half-cycle correction. The
cost of AS is not discounted in the first year.
1
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LDRBT = low-dose-rate brachytherapy, EBRT = external beam radiotherapy, RP = radical prostatectomy, AS = active surveillance
The overall annual cost to the MBS of treating men according to scenario 2 is
$28.934 million. The cost to the MBS of managing 20% of men diagnosed with Gleason
≤ 6 prostate cancer with AS is not insubstantial, for two reasons. First, the monitoring of
men while on AS is entirely performed in an outpatient setting; therefore, 85% of the MBS
fee will be borne by Medicare. Secondly, scenario 2 assumes that one-third of men who
ultimately receive active treatment will select EBRT, which is more than 80% funded by
the MBS.
The overall discounted annual cost to the Australian healthcare system of treating 5,000
men according to scenario 2 is $65.684 million. While 11% of men are initially managed
with AS, this component of management is responsible for only 7% of the total costs.
The acceptability of AS to patients and clinicians will affect both the uptake of and
persistence with AS. It remains unclear how acceptable AS is within Australian culture. For
this reason, a study with a high rate of patients moving from AS into active treatment was
used for the base case cost estimate (van den Bergh et al 2009), which in turn will result in
a conservative estimate as presented in Table 22. The figure of 20% AS among men
diagnosed with Gleason ≤ 6 prostate cancer is sourced from data gathered between
October 2000 and October 2002 (Smith et al 2010), which predates the initiation of
several international AS studies and may underestimate its current utilisation in the
community. However, the data also largely predate the introduction of LDRBT and
robotic prostatectomy, two treatments that may appeal to younger men and impact on
the proportions of men opting for AS. To represent the uncertainty surrounding the
proportion of men opting for and persisting with AS, overall costs to the Australian
healthcare system associated with different rates of participation in AS and treatment-free
survival are presented in Table 23.
Table 23
Total cost to the Australian healthcare system of treating 5,000 men with localised prostate
cancer for different rates of active surveillance (AS) and different likelihoods of opting out of
AS
Uptake of active surveillance in Australia
Source of treatment-free survival ratesa
0%
Soloway et al (2010)
$68,267,098b
van den Bergh et al (2009)
van den Bergh et al (2009) + 50%
20%
30%
50%
$64,180,846
$62,137,719
$58,051,467
$65,684,255c
$64,392,833
$61,809,990
$67,076,049
$66,480,525
$65,289,476
Soloway et al (2010) published a Kaplan-Meier treatment-free survival curve. The extracted 5-year and 10-year treatment-free survival
rates were 82.5% and 74.0% respectively. Van den Bergh et al (2009) published tabled data of yearly actuarial rates of treatment-free
survival with 5-year and 10-year rates of 62% and 43%. To calculate a higher rate of men opting out of AS, a hypothetical treatment-free
survival rate was calculated to represent 50% more men choosing active treatment than in the van den Bergh study each year. This
hypothetical situation results in a 5-year and 10-year treatment-free survival of 43% and 14.5% respectively. Figure 6 displays the actuarial
treatment-free survival curves sourced from Soloway et al 2010 and van den Bergh et al 2009, and the hypothetical treatment-free survival
rate used in this costing; bThe disparity between the cost of no AS in this table and the total cost in scenario 1 is due to the simplification of
the follow-up costing—resulting in a fixed follow-up cost of $121.80 per year; c The base case (scenario 2) is presented in Table 22.
a
Irrespective of the proportion of men remaining under AS, the overall discounted cost of
managing men with AS is less than the cost of immediate treatment. If 20% of men opt
for AS, and 74% of those men remain under AS for 10 years, as was reported in the
Soloway et al 2010 study, the total discounted cost to the Australian healthcare system
would be over $4 million less than if no men opted for AS and $1.5 million less than if
men opted out of AS at the base-case rate (57%) by 10 years.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
It is important to recognise that the overall costs of an AS protocol will be sensitive to
the ongoing costs of monitoring patients. More frequent biopsies or scans will markedly
increase the cost of managing men with AS; however, monitoring costs would need to
increase in the base case between four- and five-fold over those used in this analysis
before AS would become more costly than immediate active treatment.
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Discussion
Is it safe?
The safety of low-dose-rate brachytherapy (LDRBT) for the treatment of localised
prostate cancer was assessed according to four criteria: the effect on urinary function; the
effect on bowel function; the effect on sexual function; and the effect on general healthrelated quality of life. A total of 14, 16, 11 and 11 comparative studies (level II – III-3
intervention evidence) were identified that evaluated the urinary side effects, bowel side
effects, sexual dysfunction and detriments in general health-related quality of life,
respectively, following LDRBT compared with at least one of: radical prostatectomy
(RP), external beam radiotherapy (EBRT) and active surveillance (AS).
Urinary side effects
The most common urinary side effect following LDRBT is a transient increase in irritative
or obstructive symptoms. In all included studies comparing LDRBT and RP, urinary
irritation was greater following LDRBT than RP. Two studies comparing LDRBT and
EBRT reported worse urinary irritation following LDRBT and two reported no difference.
Most studies reported irritative symptoms using mean results from questionnaires, and
precise rates of symptoms could not be extracted.
Urinary incontinence was less common among men receiving LDRBT and EBRT than
men receiving RP. Immediately following treatment, urinary incontinence was reported
by up to 68.4% of men receiving RP and up to 17% of men receiving LDRBT. By
3 years, differences between the treatments were more modest, with up to 12.3% of men
receiving RP and 7% of men receiving LDRBT continuing to experience urinary
incontinence. Urinary incontinence following EBRT and in men receiving AS was
infrequent, with incontinence at 3 years in up to 2.7% for EBRT and 3.4%t for AS.
Studies did not distinguish between types of incontinence and it is possible that
‘incontinence’ following radiation treatments may represent urgency rather than lack of
control.
Urinary retention was more frequent following LDRBT than RP. The proportion of men
with urinary retention reported by comparative studies varied between 9% and 15%
among men treated with LDRBT, and zero and 4% among men receiving RP. One study
reported no urinary retention among EBRT patients and no study reported urinary
retention rates in men undergoing AS.
Urethral stricture was reported in between 0.15% and 14% of men receiving LDRBT, in
6.5% of men receiving RP and in 2% of men receiving EBRT. Due to the small number
of eligible studies reporting on urethral stricture following treatment, it is difficult to
conclude whether there is a difference between treatments. Rates of urethral stricture
following LDRBT, EBRT, RP and AS could not be assessed in this review.
In studies that used validated questionnaires to report urinary function, urinary bother or
scores that combined the two, the differences were usually small or questionable, or data
were presented in such a way as to make assessment difficult. In one study that showed a
large difference in urinary function between LDRBT and RP (Hashine et al 2008), the
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questionnaire was primarily designed to capture detriments in urinary-related quality of life
associated with incontinence, and was likely to be less sensitive to irritative and obstructive
urinary symptoms. Both urinary function and urinary bother scores slightly favoured
radiation treatments over surgery, although the magnitude of difference could not be
ascertained in this review due to the variability of the results and the incompatibility of the
questionnaires used in different studies. Only one study included men managed with AS
(Smith et al 2010), and a proportion of the men received active treatment during the
follow-up period; therefore, AS could not be assessed in this review.
Bowel side effects
Bowel side effects were poorly reported by most comparative studies that primarily used
either a patient-reported questionnaire score or a clinician-reported side effects scale to
represent overall detriments in bowel function following treatment. Bowel side effects
results varied across studies, with some studies reporting a difference between treatments
and others showing minimal or no difference. Importantly, no study reported worse
bowel symptoms following RP compared with LDRBT, and only one study reported
worse bowel symptoms following LDRBT compared with EBRT.
Worsening of faecal incontinence was reported in 2% and 8.9% of men at 2 years
following RP and LDRBT respectively. Worsening of rectal bleeding occurred in 15.1%
of men receiving LDRBT, and no man receiving RP reported a worsening of rectal
bleeding, at 2 years. Bloody stools were reported by 17% of men compared with 12% of
men at a mean of 16 months following EBRT and LDRBT respectively.
Of studies reporting on bowel function questionnaire components or clinician-rated side
effects, men receiving RP tended to have better bowel function following treatment than
men receiving LDRBT, who in turn had better bowel function than men receiving EBRT.
In a multivariate analysis, adjusting for baseline characteristics, the largest comparative
study reported that treatment was significantly associated with bowel function up to
2 years. The overall modelled differences in bowel function were small and of
questionable clinical importance. However, the modelling technique may be insensitive to
large disparities in bowel function early after treatment, with UCLA-PCI bowel function
scores of 75, 68 and 60 at 3 months following treatment with RP, LDRBT and EBRT
respectively. The same study also reported a significant difference in UCLA-PCI bowel
bother scores, with LDRBT an average of 7.1 points higher (less bother) than EBRT, and
RP an average of 9.4 points higher than EBRT, on a scale of 0–100 and adjusting for
baseline characteristics. A large Australian cohort study also adjusted for baseline
characteristics and found worse bowel function following treatment in men receiving
EBRT, but not RP or LDRBT, compared with an age-matched cohort without prostate
cancer. Interestingly, bother from bowel symptoms increased for all treatments although
more severely for men receiving EBRT.
Without the reporting of incidences of specific bowel side effects such as incontinence,
pain, bloody stools, constipation and diarrhoea, it is difficult to interpret differences in
bowel symptom scores. It is likely that men receiving LDRBT experience more bowel side
effects and bother associated with side effects than men receiving RP. It is also likely that
men receiving LDRBT experience fewer bowel side effects and bother than men receiving
EBRT. However, several studies report no difference and one study reports fewer side
effects following EBRT than LDRBT. Only one study regards men managed with AS but,
as a proportion of the men crossed to active treatment in the follow-up
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period, an accurate assessment of the bowel side effects of AS could not be undertaken in
this review.
Sexual dysfunction
Perhaps more than urinary or bowel function, erectile function varies manifestly with age.
An Australian survey found that 11.9% of men aged 50–59 years were unable to achieve
an erection adequate for intercourse, and this increased markedly to 42.3% at age 60–
69 years and 64.2% for men aged 70–79 years (Pinnock et al 1999). For studies
comparing the erectile function of two groups, it is therefore vital that the groups are of a
similar age. Merely excluding patients who were not potent before treatment from
analysis will not remove the bias associated with the natural onset of erectile impotence
with age if groups are not comparable at baseline. In a non-randomised setting, an
additional source of bias when considering erectile function as an outcome may be that
patients most interested in preserving sexual function will choose treatments that are
advertised as offering higher rates of post-treatment potency. This will tend to exaggerate
the potency rates for treatments selected by potent men who may be highly motivated to
undertake erectile rehabilitation following treatment. The post-treatment use of
phosphodiesterase type 5 (PDE5) inhibitors will also be a strong source of bias if use is
not equal between groups.
In comparative studies the proportion of men reporting post-treatment potency among
those who were potent before treatment varied from 67% to 95.7% following LDRBT
and 51% to 68.8% following EBRT. At 18 months following RP, 83.3% of men who
were sexually active before treatment reported a diminished ability to achieve or maintain
an erection, compared with 45.8% of men who received LDRBT.
Sexual function, as reported by patient questionnaires, was consistently greater among
men following LDRBT or EBRT than among men following RP, with the exception of
two studies that showed no difference. In a large Australian cohort, adjusting for baseline
function, demographics and comorbidities, sexual function was poorer following either
nerve-sparing or non-nerve-sparing RP than EBRT or LDRBT. In studies comparing
sexual function following EBRT and LDRBT, either no difference was reported or
baseline function was not accounted for, introducing substantial bias into the results.
Only one study compared LDRBT with AS and found no difference at 3 years after
adjusting for age, baseline sexual function, comorbidities and demographics. However, a
proportion of the men managed with AS crossed to active treatment during the follow-up
period and this will strongly confound the results. Sexual function following AS could not
be adequately assessed by this review.
There are conflicting reports regarding sexual bother following treatments, with one
study reporting greater bother among men receiving RP than LDRBT after 12 months,
and one study reporting no difference at a mean of 4 and 3.5 years following RP and
LDRBT respectively. This suggests that bother may reduce over time.
General health-related quality of life
Health-related quality of life following treatment for prostate cancer is likely to reflect
impairments due to side effects of treatments. Localised prostate cancer is largely
asymptomatic; therefore, treatments are aimed at eradicating prostate cancer and not at
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improving the quality of life of a man with prostate cancer. In the longer term differences
in health-related quality of life (HRQoL) will be contingent upon treatment effectiveness,
with men who have recurrent disease reporting lower utility than those who remain
disease free. For low-risk prostate cancer, differences in effectiveness are unlikely to
manifest in the short term, and hence this review has considered HRQoL to be a facet of
safety rather than effectiveness.
More than half of all comparative studies considered eligible for this review reported on
general HRQoL using a patient questionnaire. Unfortunately, the instrument used to
measure HRQoL varied among the trials. Four different questionnaires (SF-36, EORTC
QLQ-C30, FACT-G and FACT-P) and several methods of presenting the results as
either global measures or compartmentalised measures of the physical, mental or a myriad
of other components make inter-study comparison of the results difficult.
Overall, there are mixed results when comparing quality of life following treatment in
men receiving LDRBT with those receiving RP or EBRT. In most cases there were no
differences or only very small differences of questionable clinical relevance among all
three treatments.
Comparing LDRBT with RP, in studies reporting on quality of life very early after
treatment, LDRBT consistently performed better than RP. However, HRQoL was no
different in most studies beyond 6 months. Interestingly, two studies reported greater
HRQoL among RP patients at 6 months and 25 months following treatment, although
neither study controlled for baseline HRQoL. Given the immediate nature of RP side
effects, and the delayed onset of LDRBT side effects as the prostate receives radiation
over a prolonged period, it is likely that small comparative reductions in quality of life
occur immediately following RP.
Comparing HRQoL following LDRBT and EBRT also returned mixed results. One study
reported significantly higher scores at 6 months for LDRBT compared with EBRT and
two studies reported worse scores for LDRBT compared with EBRT at 1 month and
2.5 years following treatment. The two remaining studies showed no difference following
EBRT and LDRBT, and were the only two studies to control for baseline HRQoL.
Only one study compared AS with HRQoL and reported no difference in either the
physical component or mental component scores of the SF-12 health survey up to 3 years
following treatment (Smith et al 2010). However, some AS patients were treated during the
follow-up period and this may have an effect on their HRQoL. The assessment of quality
of life in men managed with AS could not be adequately considered in this review.
Overall, there is a lack of high-quality evidence to determine whether there are any
differences in post-treatment HRQoL between LDRBT, RP and EBRT. While there may
be some small differences early after treatment, any differences between treatments appear
to be negligible by 6 months.
Summary of the body of evidence for the safety of low-dose-rate
brachytherapy
The body of evidence included in this assessment was appraised according to the
NHMRC’s guidance on clinical practice guideline development (NHMRC 2009). The
body of evidence matrix for studies comparing LDRBT with EBRT is presented in Table
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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24. The evidence-base was poor, containing studies of level III-2 to level IV interventional
evidence with moderate to high risk of bias. Despite attempts at matching populations or
controlling for potential confounders statistically post hoc, no study satisfactorily removed
the effect of patient or clinician treatment selection. Comparing LDRBT with EBRT,
there was some inconsistency with results, which is likely to represent genuine uncertainty
regarding most safety outcomes. Therefore, given that the differences between LDRBT
and EBRT regarding most safety outcomes appear to be minimal, the clinical impact of
this assessment is judged to be slight. All studies were performed in developed countries
and largely used techniques common in Australia. It is likely that some studies were
performed in centres of high patient volume and may report better outcomes than centres
of lower patient volume in Australia, although, overall, the generalisability and applicability
of the results for LDRBT compared with EBRT are deemed to be good.
Table 24
Assessment of body of evidence for the safety of low-dose-rate brachytherapy compared with
external beam radiotherapy for the treatment of localised prostate cancera
Component
A
B
C
D
Excellent
Good
Satisfactory
Poor
Level IV studies, or
level I to III studies
with high risk of bias
Evidence-base
Some inconsistency
reflecting genuine
uncertainty around
clinical question
Consistency
Clinical impact
Slight or restricted
Generalisability
Population(s) studied in
body of evidence are
similar to the target
population
Applicability
Applicable to Australian
healthcare context with
few caveats
a
For an explanation of this table refer to ‗Assessment of the body of evidence‘ on page 30; Source: NHMRC (2009)
The body of evidence matrix for studies comparing LDRBT with RP is presented in
Table 25. The evidence-base was satisfactory, containing a moderate-quality randomised
controlled trial (level II evidence) and level III-2 to level IV interventional evidence
studies with moderate to high risk of bias. Where baseline characteristics of comparative
study arms were not matched, or baseline function was not adjusted for statistically, it was
sometimes possible to predict the direction of the confounding on the study outcome;
however, baseline function was not always known. Overall, most studies presented
consistent results for urinary incontinence, irritative or obstructive symptoms, bowel
symptoms and erectile dysfunction. The magnitude of the differences between the arms
was not consistent, with some studies showing little or no difference, but the direction of
the difference in studies reporting a difference was largely the same. Overall consistency
for studies comparing LDRBT with RP was deemed to be good. Given the differences in
urinary, bowel and sexual symptoms following the treatments, the clinical impact of this
evidence is judged to be substantial. However, a substantial clinical impact does not imply
that all patients would clearly select one treatment over another. Rather, the disparate side
effect profiles of each treatment will need to be considered by patients and clinicians
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when selecting a treatment that will result in the least adverse outcomes for individual
patients. Therefore, for a patient with a strong aversion to a particular side effect, the
evidence may have a substantial clinical impact. All studies were performed in developed
countries with varying levels of screening-detected prostate cancer. In one study the
surgical procedure was different to that primarily performed in Australia, and some
studies may have taken place in centres with high patient volume. Overall, the
generalisability and applicability of studies to the Australian population and the Australian
healthcare system is judged to be good.
Table 25
Assessment of body of evidence for the safety of low-dose-rate brachytherapy compared with
radical prostatectomy for the treatment of localised prostate cancera
Component
A
B
C
D
Excellent
Good
Satisfactory
Poor
Level III studies with
low risk of bias, or level
I or II studies with
moderate risk of bias
Evidence-base
Consistency
Most studies consistent
and inconsistency may
be explained
Clinical impact
Substantial
Generalisability
Population(s) studied in
body of evidence are
similar to the target
population
Applicability
Applicable to Australian
healthcare context with
few caveats
a
For an explanation of this table refer to ‗Assessment of the body of evidence‘ on page 30; Source: NHMRC (2009)
The body of evidence matrix for studies comparing LDRBT with AS is presented in Table
26. Only one included study identified an AS arm. The study was of a large Australianbased cohort that captured two-thirds of men aged less than 70 years diagnosed with
localised prostate cancer over a 2-year period in New South Wales. Baseline characteristics
were adjusted for statistically. Ultimately, treatment was selected rather than randomised,
and a proportion of men managed with AS received active treatment during the follow-up
period. Therefore, the evidence-base is judged to be poor, containing only one level III-2
study with a moderate to high risk of bias. The lack of evidence for the safety of AS, in
comparison with LDRBT, must render the observed clinical impact of this evidence as
slight. As mentioned, the study was large and based in Australia, collecting data from
patients treated in both high- and low-volume centres. Some data from centres with
higher than average volumes were not collected; however, overall, the generalisability and
applicability of the evidence is excellent.
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Table 26
Assessment of body of evidence for the safety of low-dose-rate brachytherapy compared with
active surveillance for the treatment of localised prostate cancera
Component
A
B
C
D
Excellent
Good
Satisfactory
Poor
Level IV studies, or
level I to III studies
with high risk of bias
Evidence base
Consistency
Not applicable (only one study involving active surveillance was identified)
Clinical impact
Slight or restricted
Generalisability
Population(s) studied
in body of evidence
are the same as the
target population
Applicability
Directly applicable to
Australian healthcare
context
a
For an explanation of this table refer to ‗Assessment of the body of evidence‘ on page 30; Source: NHMRC (2009)
Other safety outcomes
There are multiple known immediate side effects of LDRBT, EBRT and RP surgery.
These may include blood loss requiring transfusion, infection, venous thrombosis,
haematoma, hernia, bowel perforation and patient death. As surgery requires a general
anaesthetic, the risks associated with general anaesthesia are also borne by the patient,
including allergic reactions, aspiration and death. LDRBT is described as a minimally
invasive procedure; however, it still carries the risk of infection and venous thrombosis. It
may also carry risks of seed migration through the bloodstream to other organs, usually
the lung; or rectourethral fistula, a catastrophic side effect requiring surgery and stool
diversion. Loss of individual seeds is not uncommon following LDRBT and they are
usually lost into the urethra and then in the urine or ejaculate, although this poses no
threat. Migration of the seeds to the lung is less common and has not been linked to
short-term adverse consequences (Ankem et al 2002).
Like prostate surgery, LDRBT is usually (although not always) delivered under general
anaesthesia. EBRT is a relatively non-invasive procedure and, while it may require the
insertion of fiducial markers to assist in the planning and accurate localisation of the
prostate, this is customarily done under a local anaesthetic. EBRT may be associated with
lethargy, nausea, and skin or mucous membrane reactions that can become infected. One
serious side effect associated with all forms of radiation treatment is the development of
second malignancies from radiation exposure. As these side effects are largely treatment
specific, and perhaps because they are far less common than urinary and bowel side
effects and sexual dysfunction, comparative studies rarely report on them in a meaningful
way. In most cases such rare side effects are reported as case reports, and have not been
captured by this review.
Three large cohort studies using data of men diagnosed with prostate cancer and entered
onto the Surveillance, Epidemiology and End Results (SEER) database in the US
compared the incidence of radiotherapy-induced second primary cancers (SPCs) among
men receiving EBRT, BT and no radiation. Two of the cohort studies involved men who
received prostate surgery. All studies used data from the same large US database and
involve overlapping populations. These studies have been excluded from this systematic
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review on the basis that it is impossible to identify the proportion of the study population
that would be eligible. It is likely that a proportion of men had PSA ≥ 10 ng/mL or
Gleason score > 7 or had non-localised prostate cancer. In addition, details of treatments
are not provided and it is not certain that the treatments delivered resemble those
required by this systematic review. In light of this, these results must be interpreted with
caution.
In one study comparing radiotherapy treatments with RP (Nieder et al 2008), men who
received EBRT or LDRBT were at an increased risk of developing bladder cancer
between 5 and 10 years following treatment, compared with RP (RREBRT = 2.26 [95% CI
1.89, 2.69], RRLDRBT = 1.64 [95% CI 1.03, 2.62]). EBRT patients, but not LDRBT
patients, also experienced an increase in rectal cancers relative to men treated with RP
(RREBRT = 1.39 [1.09, 1.79]). Nieder et al (2008) also reported on SPCs occurring earlier
than 5 years following treatment and found that men treated with either EBRT or
LDRBT had a raised likelihood of developing bladder cancer; however, this result should
be considered with caution. Some research indicates that radiation-induced cancers have a
latency period of 5–15 years (Jao et al 1987; Thompson et al 1994). It is possible that the
increased incidence of bladder cancer among LDRBT and EBRT patients compared with
RP patients within the first 5 years suffers from confounding. Men treated with RP
appear to be substantially younger than men treated with either EBRT or LDRBT,
although the authors have not compared the ages of the cohorts statistically. The authors
do, however, adjust for age, race, prostate cancer stage and grade, and year of treatment
in a multivariate Cox regression analysis. Compared with men treated with RP, RR EBRT =
1.72 (95% CI 1.55, 1.90) and RRLDRBT = 1.23 (95% CI 1.01, 1.50). However, this statistic
still includes bladder cancers that are unlikely to be linked to treatment for prostate
cancer. Importantly, when compared with the expected incidence of bladder cancers
within the entire SEER database, there was no difference in the incidence of bladder
cancer in men treated with LDRBT (RRLDRBT = 1.10 95% CI 0.92, 1.31), while a
significant difference remained in men treated with EBRT (RREBRT = 1.42 95% CI 1.34,
1.50).
In a study comparing the odds of developing SPCs among men receiving radiation with
those receiving no radiation (Moon et al 2006), adjusted for age, stage and prostate cancer
grade, EBRT patients were at increased odds of developing cancer of the colon, rectum,
bladder and non-Hodgkin lymphoma, with odds ratios of 1.26, 1.60, 1.63 and 1.26
(p<0.05) respectively. Men receiving LDRBT as a monotherapy had raised odds of
acquiring bladder cancer compared with men not receiving radiation, although the
difference was not statistically significant. Compared with men who did not receive
surgery, men receiving RP had reduced odds (ORRP = 0.78, p<0.05) of developing
bladder cancer following treatment. Importantly, only cancers that were diagnosed more
than 5 years following treatment were included in the analysis, thereby excluding cancers
that are unlikely to be linked to treatment for prostate cancer.
In one final study comparing the incidence of SPCs among men treated for prostate
cancer with men who received no radiotherapy and no surgery for prostate cancer,
patients who received EBRT alone were 1.263 [95% CI 1.167, 1.367] times more likely to
acquire an SPC after 5 or more years (Abdel-Wahab et al 2008). SPCs detected earlier than
5 years following treatment were excluded from the analysis. For men treated solely with
EBRT, the rate of second malignancies did not appear to change with time. The incidence
of SPC increased with time following LDRBT and EBRT combined with LDRBT; and
after 9 years following treatment, the mean hazard ratio for both LDRBT and
combination EBRT were approximately that of EBRT alone. One potential
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confounder in this study is that men receiving EBRT alone tended to be older than
LDRBT or combination EBRT patients, and hence other malignancies may be more
prevalent in this group. This study reported an additional 162 cancers per 100,000 men
that may have been radiation induced, but cautioned that some of the increased cancer
incidence may be due to an inherent increased risk of cancer within the population
receiving radiotherapy.
All three studies have serious limitations. The SEER database does not contain
information on smoking status, which is known to increase the risk of bladder cancer
three-fold (Zeegers et al 2002). Also, the studies do not provide treatment details; in
particular, they do not report on radiation dosage or the isotope used for interstitial
LDRBT (although the isotope used for LDRBT is unlikely to make any difference to the
rate of second malignancies).
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Is it effective?
Primary effectiveness outcomes
The study by Zhou et al (2009) reported on all-cause survival after radical prostatectomy
(RP), low-dose-rate brachytherapy (LDRBT) and external beam radiotherapy (EBRT).
Actuarial 7-year survival was higher for LDRBT patients (82%) than EBRT patients
(72%), and survival for RP patients was 89%. Comparing the treatment modalities with
‘no treatment’ as the reference, hazard ratios (Cox regression) for RP, LDRBT and EBRT
showed that any treatment was preferable over the option of ‘no treatment’ (p<0.0001).
LDRBT was not directly compared statistically with the other treatments; however, the
confidence intervals for the hazard ratios for LDRBT and EBRT did not overlap,
suggesting a significantly lower likelihood of dying from any cause among LDRBT
patients than EBRT patients. Despite correcting for multiple risk factors including
Gleason score, comorbidities and age, treatment assignment was not randomised and the
effect of confounding cannot be ruled out. Given that the confidence intervals for the
hazard ratios for RP and LDRBT did overlap, it is likely that these treatments are not
significantly different, even though Kaplan-Meier analysis gave overall survival of 89% for
RP and 82% for LDRBT.
Prostate cancer specific survival at 7 years was high among all treatment groups, although
RP patients had the best survival (98%), compared with LDRBT (97%) and EBRT
(94%). Given the older age of men who are treated for prostate cancer, cancer-specific
survival rather than overall survival may be a more accurate representation of treatment
effectiveness. Cancer-specific survival for RP and LDRBT is comparable when
adjustment is made for clinical stage, Gleason score and other risk factors, while EBRT
outcomes are slightly less favourable. Hazard ratios for prostate cancer specific survival
indicated that RP and LDRBT were significantly more effective than ‘no treatment’
(p<0.0001 and p=0.018 respectively). However, the confidence intervals for all
treatments overlapped. Wide confidence intervals in the LDRBT and EBRT groups were
apparent—potentially due to small patient numbers—and so accurate comparisons of
cancer-specific survival between the treatments cannot be made.
The analysis by Zhou and colleagues (2009) attempted to control for important risk
factors, but the large differences observed in overall survival are unlikely to represent real
differences in treatment effectiveness. The results for prostate cancer specific survival,
which only show small differences between the treatments, indicate that disparities in
overall survival are a consequence of unknown or unaccounted-for confounding factors.
Furthermore, no information on PSA was obtainable from the databases sourced for this
study. The authors admit that pre-treatment PSA > 10 ng/mL is an important risk factor
for prostate cancer specific death, and the lack of PSA data makes meaningful conclusions
about the effectiveness of the various treatment modalities difficult. International
guidelines contraindicate LDRBT for patients with PSA > 10 ng/mL, whereas patients
with a broader range of PSA values are treated with RP and EBRT. Therefore, selection
of patients with lower PSA values for LDRBT will result in
improved outcomes for LDRBT patients compared with RP and EBRT. The extent of
any such bias could not be measured.
Cancer stage is correlated with PSA (Partin et al 2001) and, while large disparities between
the treatment groups in terms of PSA may be reflected in differences in recorded stage,
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only small differences were noted. Therefore, it is unlikely that baseline PSA levels
differed dramatically among patient groups.
The database from which Gleason score and stage data were sourced is routinely updated
following RP, and evidence from case series suggests that 30–40% of biopsies are assigned
a higher grade on review (Capitanio et al 2009). This means that, while a true Gleason
score will be known for RP patients, a proportion of LDRBT and EBRT
patients assigned a score of Gleason 6 will in fact be Gleason 7, and some of those with a
biopsy indicating Gleason 7 will have a true score of Gleason 8. Since it is likely that, in a
proportion of patients thought to be low-risk, the biopsy Gleason score will
underestimate the true Gleason score, the effectiveness of LDRBT and EBRT may
appear reduced in comparison with RP. Although the direction of any such bias is likely
to work against LDRBT, cancer-specific survival was found to be similar among LDRBT
and RP patients.
Another limitation of the study by Zhou et al (2009) was adjustment for comorbidity
using the Charlson Index, which provides measures based on hospital admissions and
outpatient visits. Other conditions for which patients did not receive medical care
(functional dependence, performance status and geriatric conditions) may have been
present, uncaptured by the Charlson Index but influencing the findings of this study.
In addition, applicability of this study to the Australian context may have some
limitations. It is probable, given the large sample size and the common use of palladium
for LDRBT in the US, that a number of patients underwent treatment with palladium.
However, one multicentre randomised study has demonstrated that iodine and palladium
yield similar results for bNED at 3 years (Wallner et al 2003), and it would not be
expected that non-prostate cancer specific survival would differ greatly on the basis of the
type of radioactive implants used for LDRBT. Whether comparable secondary measures
(bNED) of effectiveness for seeds with different radioactive properties translate to
clinically comparable prostate-specific survival in the long term is uncertain on the basis
of the evidence available for this review.
There also remains the concern that an unknown proportion of patients did not meet the
eligibility criteria for this review. Despite stratified results, which made data for patients
with localised disease available for separate analysis, an unknown number of these patients
had Gleason scores in the range 8–10. These patients may have influenced the
outcomes of the study and would not be eligible for LDRBT according to current criteria
in Australia.
Data from the lower quality studies (Pickles et al 2009; Vicini et al 2002) did not refute
the conclusions given above.
Despite the potential risk of bias in Zhou et al (2009), the directions of the most important
biases in this study are not in favour of LDRBT. However, LDRBT still performed
acceptably under such circumstances. Randomised controlled trials capable of addressing
known and unknown confounding factors have rarely been undertaken in this area due to
strong patient preferences for particular treatment options and selection for side effect
profiles. On the basis of the results, it is reasonable to conclude that LDRBT is no worse
than RP and EBRT in terms of 7-year overall and disease-specific survival.
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Secondary effectiveness outcomes
Biochemical disease-free survival
The randomised controlled trial by Giberti et al (2009) reported 5-year bNED for 174 out
of the 200 recruited low-risk prostate cancer patients undergoing RP or LDRBT. In the RP
and LDRBT groups, 5-year bNED was 91% and 91.7%, respectively, but no
definition of bNED was provided.
The main strength of the study by Giberti et al (2009) was the randomised design that
provided patient groups with similar prognostic variables and other baseline
characteristics for direct comparison. However, there is no evidence of time-to-event
analysis, and statistical methods used to compare biochemical recurrence between men
treated with RP and LDRBT may be inappropriate. The authors reported that a chisquared analysis or Fisher’s exact test was used to compare 5-year bNED, and no
adjustment for losses to follow-up occurred. The authors did not discuss the
characteristics of patients lost to follow-up and no sensitivity analysis was performed;
therefore, the relapse status of patients lost to follow-up is unaccounted for, which could
influence bNED outcomes in an unknown direction. Importantly, the definitions of
biochemical recurrence were not reported and therefore comparisons of bNED between
men treated with RP and those treated with LDRBT may be influenced by systematic
differences in the sensitivity or specificity of the definitions used for recurrence (Nielsen
et al 2008).
Wong and colleagues (2009) reported 5-year bNED for 853 patients undergoing LDRBT
or EBRT in two modalities—3D conformal and intensity modulated radiotherapy
(IMRT)—and no significant differences were observed between the treatments. As with
all studies in the evidence-base, this study was subject to physician and patient
preferences for treatments and, consequently, the degree of bias that may have been
introduced is uncertain. The distribution of palladium-treated LDRBT patients is
unknown and therefore it is difficult to judge whether the majority of low-risk patients
did in fact receive treatment with iodine seeds. Given that palladium is not currently
available in Australia, the generalisability of these results may be questionable. Across all
treatments only small numbers of patients recurred biochemically and, for low-risk
patients, LDRBT and either 3D-CRT or IMRT appeared equally effective.
Beyer & Brachman (2000) found no statistically significant differences between patients
treated with LDRBT or EBRT for either 5-year or 7-year freedom from biochemical
recurrence. Prognostic variables (PSA and Gleason score) were taken into account in the
analysis, but the authors indicate that bNED at both 5 and 7 years for low-risk patients
(PSA < 10 ng/mL) in both the EBRT and LDRBT groups was lower than observed in
other studies with similar patients. The authors postulate that pathological assessment of
biopsy specimens may be inconsistent and inaccurately reflect patients’ true Gleason
scores. They support this hypothesis by reporting that biochemical recurrence in their
study did not stratify well by Gleason score and that in wider practice 40–76% of
specimens are assigned a different (often higher) score on review. However, undergrading of Gleason scores was likely to be uniform between the treatment groups (EBRT
and LDRBT) and therefore unlikely to affect treatment comparisons.
Pickles et al (2010) used a matched-pair design in patients treated with LDRBT and
EBRT. Five-year bNED was higher among LDRBT patients (94%) than EBRT patients
(88%) for the low-risk group (p<0.001). For the intermediate-risk group, bNED was
100% for LDRBT and 78% for EBRT patients (p≤0.016). Overall, bNED was 95.2% for
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LDRBT and 84.7% for EBRT patients (p<0.001), indicating that only 5% of LDRBT
patients relapsed while 15% of EBRT patients experienced biochemical recurrence.
However, the PSA doubling time among those who experienced biochemical relapse was
a median of 6 months in the LDRBT group and 24 months in the EBRT group
(p<0.001). The slower PSA doubling time in EBRT patients could well reflect the
persistence of local disease caused by under-dosage with EBRT, while faster PSA
doubling among the few LDRBT patients who experience relapse is likely to indicate
failure resulting from metastatic disease outside the irradiated treatment area. In a review
article (Ganswindt et al 2005), low-risk patients benefited from dose escalation up to 70–
72 Gy; therefore, less than one-quarter of patients in the analysis by Pickles et al (2010)
were likely to have been optimally dosed (the median dosage was 68 Gy and only 25% of
EBRT patients received a dosage in excess of 68 Gy).
The main strengths of the study by Pickles and colleagues (2010) were the matched-pair
design and the ability to obtain PSA data and to stratify results on the basis of low- and
intermediate-risk groups. Patients were matched on all key predictors of bNED, such as
Gleason score, PSA level, clinical stage and percentage of positive cores, but not age.
Despite age being an important baseline characteristic when considering all-cause
survival, it is far less likely to influence secondary measures of disease-specific survival
such as bNED. There are, however, some limitations. In particular, it is not clear whether
the relatively small number of patients in the matched analysis would be representative of
the general Canadian population, or be generalisable to Australia. However, the authors
did conduct a secondary analysis of 601 patients deemed eligible but who were not
successfully matched. Five-year bNED for the unmatched cohort (95.3% and 81% for
LDRBT and EBRT patients respectively) was similar to that observed for the matched
cohort (95.2% and 84.7% for LDRBT and EBRT patients respectively), but statistical
significance was not reported. Even if a strong statistical difference had been reported, it is
highly unlikely that a post-hoc analysis would increase the external validity of the results.
On the contrary, such an analysis would reintroduce known confounders, including age,
PSA and cancer stage, for which matching was able to adjust.
Studies that considered bNED were all of moderate quality and the majority (Beyer &
Brachman 2000; Giberti et al 2009; Wong et al 2009) found no differences between
prostate cancer treatments. Some evidence suggested that bNED may be as much as 20%
greater among LDRBT patients compared with EBRT patients when considering
intermediate-risk patients but, overall, the difference is closer to 10% (Pickles et al 2010).
Given that three-quarters of the participants in the EBRT arm received suboptimal
dosages, these results need to be interpreted with caution. The other studies that
considered bNED found no significant differences between treatments or gave no
evidence of a valid statistical comparison (Vicini et al 2002). All studies that assessed
bNED are likely to have been biased, but the extent of the bias is unable to be quantified
and its direction is unknown.
Summary of the body of evidence for the effectiveness of low-dose-rate
brachytherapy
The body of evidence included in this assessment was appraised according to the
NHMRC’s guidance on clinical practice guideline development (NHMRC 2009). The
body of evidence matrix for studies comparing LDRBT with EBRT and RP is presented
in Table 27. No studies that included active surveillance (AS) as a comparator were
identified and therefore AS was not assessed. In studies that compared LDRBT with
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EBRT and RP, the evidence-base was satisfactory, containing one study of level II and four
studies of level III interventional evidence with low to moderate risk of bias. For studies that
presented primary effectiveness outcomes, the main source of potential bias was routine
updating of Gleason scores for RP patients (Zhou et al 2009); however, despite this, LDRBT
still performed similarly to RP. The studies that assessed secondary outcomes were subject to
biases from physician and patient preferences, and other biases for which the size and
direction of influence could not be determined. Most of the
studies were consistent in showing that primary and secondary effectiveness outcomes for
LDRBT were at least no worse than for RP or EBRT. In one instance (Pickles et al
2010) bNED results appeared more favourable for LDRBT than EBRT, but this was possibly
a reflection of suboptimal radiation dosing among EBRT patients. Given that there was
uncertainty regarding the extent and direction of bias in the studies that presented secondary
effectiveness, and only one moderate-quality study on primary effectiveness reported
outcomes for LDRBT, EBRT and RP, the clinical impact of this evidence is limited. All
studies were undertaken in developed countries and the majority of patients had localised
prostate cancer and were generalisable to the target population within Australia. However, an
unknown proportion of LDRBT patients studied by Zhou et al (2009) were likely to have
been treated with palladium. Consequently, the results are applicable to the Australian
healthcare context only with some reservations.
Table 27
Assessment of body of evidence for the effectiveness of low-dose-rate brachytherapy
compared with external beam radiotherapy and radical prostatectomy for the treatment of
localised prostate cancera,b
Component
A
B
Excellent
Good
D
Satisfactory
Poor
Level III studies with
low risk of bias, or level
I or II studies with
moderate risk of bias
Evidence-base
Consistency
C
Most studies consistent
and inconsistency may
be explained
Slight or restricted
Clinical impact
Generalisability
Population(s) studied in
body of evidence are
similar to the target
population
Applicability
Applicable to Australian
healthcare context with
few caveats
a For
b No
an explanation of this table refer to ‗Assessment of the body of evidence‘ on page 30; Source: NHMRC (2009)
studies for active surveillance were identified and therefore this comparator was not assessed in the body of evidence matrix.
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What are the economic considerations?
Cost and cost-effectiveness
One health technology assessment (HTA) combining the findings of three systematic
reviews and three comparative studies assessed the economic considerations of low-doserate brachytherapy (LDRBT) as a treatment for localised prostate cancer. No studies of the
costs of LDRBT compared with external beam radiotherapy (EBRT), radical
prostatectomy (RP) or active surveillance (AS) in an Australian setting were identified.
Two of the comparative studies reported similar costs associated with LDRBT compared
with RP and one reported that costs were substantially greater with LDRBT. While all
three studies describe RP and LDRBT procedures that are similar to those performed in
Australia, the transferability of costs from international studies is unclear.
One HTA combined the safety results from three systematic reviews of LDRBT and
proton beam therapy, RP and AS, and IMRT (a form of EBRT). The HTA and
systematic reviews were all undertaken by the Institute for Clinical and Economic
Review. The report contained a cost–utility analysis of the treatments using a Markov
model. The transition probabilities and health state utilities were sourced from the
literature, and costs were sourced from published studies, interviews with clinicians and
Medicare. The three systematic reviews informed the rates of treatment-related side
effects for each of the treatments.
The base case for the model found that, compared with RP, LDRBT resulted in 0.3 more
quality adjusted life years (QALYs) at a reduced cost. IMRT also resulted in more QALYs
(0.27) although at an incremental cost of US$9,513, resulting in an incremental cost per
QALY of US$35,233. AS provided 1.15 more QALYs than RP at an incremental cost of
US$2,074 or US$1,803 per QALY.
The model assumes that all treatments are equally effective regarding survival outcomes,
and hence any difference in QALYs following treatment will be due to the side effects of
each treatment. Importantly, equivalent effectiveness has been reported in this current
review. As mentioned, the rates of the side effects were informed by the three systematic
reviews undertaken by the Institute for Clinical and Economic Review. Unfortunately, the
systematic reviews were of moderate to low quality and relied heavily on low-level
intervention evidence (primarily case series).
Given the overall similar cost-effectiveness of all treatments, accepting the substantial
uncertainties surrounding the model, it is difficult to conclude the superiority of any one
treatment from an economic viewpoint. In particular, the model has costed treatments
within the US, which may differ markedly to the costs for the same treatments in
Australia.
The generalisability of health economic data from country to country is limited by the
degree of similarity between health systems and populations. For the most part,
populations and disease characteristics are similar across developed countries; however,
variations in wages, methods of healthcare provider reimbursement, physician liability,
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available technology and general organisational differences may limit the transferability of
cost data from one country to another (Welte et al 2004).
Financial impact analysis
Estimating the likely number of men who would be eligible for 125I LDRBT is difficult
given the lack of published national epidemiological data stratifying men by cancer stage
or grade. However, using data from two recently published studies, one from South
Australia (Beckmann et al 2009) and one from New South Wales (Smith et al 2010), the
likely number of men eligible for LDRBT has been estimated at 5,000 in 1 year. This
calculation has been addressed in the section on ‘Potential utilisation’ on page 12. The
costs associated with the treatment of men with Gleason 7 prostate cancer are higher, to
reflect a greater need for pre-treatment staging scans and the increased likelihood of
LHRHa use among men receiving EBRT. Therefore, it is important to estimate the likely
proportion of men with Gleason ≤ 6 and Gleason 7 cancer among men with localised
prostate cancer. Our best estimate of this ratio is that 55% of men are diagnosed with
Gleason ≤ 6 and 45% with Gleason 7 (Shao et al 2009).
All costs are discounted at 5% per year with a half-cycle correction, with the exception of
AS costs accrued in the first year.
Scenario 1—BT, EBRT and RP
Overall, the costs associated with LDRBT, EBRT and RP are similar. Assuming that 70%
of men treated with LDRBT and 75% with RP are treated in the private healthcare sector,
the current annual cost of treating 5,000 men with LDRBT, EBRT and RP (ie excluding
AS) is estimated at $66.727 million. LDRBT is marginally more costly than RP, with an
incremental cost of LDRBT per patient of $37; and marginally less costly than EBRT,
with an incremental cost saving per patient of $105. Obviously, this difference
will be sensitive to even small variations in practice regarding work-up, treatment or posttreatment monitoring.
Despite similarities in overall cost, the source of funding for each treatment differs
substantially. The MBS is responsible for a greater portion of the cost associated with
EBRT, given that it is the only treatment to be delivered entirely on an outpatient basis.
LDRBT and RP are performed in a hospital environment and a greater proportion of
their overall cost is borne by state/territory governments or by the patient/private
insurer. In addition, the largest single expenditure for LDRBT is the cost of the BT seeds,
currently listed at approximately $7,000 per patient, while the largest expenditure for RP
is the cost of hospitalisation, which is between $8,685 (not including procedural costs) in
a private setting and $13,874 (including procedural costs) in a public setting. Both of these
expenses are borne by either the patient or his private insurer in a private hospital setting,
or by the state/territory governments in a public hospital setting. While the cost to the
MBS is greater for EBRT, the substantial saving to the MBS when patients are treated
with LDRBT and RP is entirely attributable to the redistribution of costs to other sectors
of the Australian healthcare system.
One important omission in this analysis is the increasing use of robot-assisted
laparoscopic prostatectomy (RALP). Costs associated with RALP are higher than with
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standard open retropubic prostatectomy and were reported as $4,71713 higher in a 2006
Australian systematic review (Medical Services Advisory Committee 2006). Therefore,
compared with LDRBT, treating men with RALP will result in an additional cost of
$4,680 per patient, borne either by the patient/private insurer in a private hospital setting,
or absorbed by the state/territory government in a public hospital setting.
Scenario 2—BT, EBRT, RP and AS
The likely utilisation of AS in Australia is uncertain. One source using data accrued from
October 2000 to October 2002 reported that 20% of men diagnosed with Gleason ≤ 6
prostate cancer initially opted for AS (Smith et al 2010). Among men with Gleason 7
prostate cancer, AS was observed in less than 3.5% in the same study. The
appropriateness of AS among men with Gleason 7 prostate cancer is unclear, and it was
decided a priori that it would not be considered an appropriate comparator for LDRBT
in men diagnosed with Gleason 7 disease. Consequently, the base case has been costed
using a 20% uptake of AS among Gleason ≤ 6 disease only, with the remaining men
diagnosed with Gleason ≤ 6 and all men with Gleason 7 prostate cancer opting equally
for one of the active treatments.
The cost of AS will be sensitive to the proportion of men opting out of AS. For the base
case it is assumed that 57% of men will opt out of AS by 10 years at the rate observed in
the study by van den Bergh et al 2009.
The overall discounted annual cost to the Australian healthcare system of treating 5,000
men with a combination of LDRBT, EBRT, RP and AS is $65.684 million. This
represents a cost saving of approximately $2.583 million over the same scenario without
the use of AS. The total cost to the MBS is $28.934 million, with over half the cost being
generated by men who initially opt for EBRT. The cost to the patient/private insurer is
$25.790 million, primarily as a result of the expenses incurred by LDRBT seeds and RP
hospitalisation in a private healthcare setting.
If the uptake of AS among men with Gleason ≤ 6 prostate cancer changes or the
retention rate of men while on AS alters, then the total overall costs of treating 5,000
considered to be eligible for LDRBT will also change. Assuming a higher treatment-free
survival, with 74% of men remaining on AS at 10 years (Soloway et al 2010), the overall
cost to the Australian healthcare system of managing 5,000 men with localised prostate
cancer decreases to $64.181 million. If, in addition to an increased retention rate while on
AS, 50% of men diagnosed with Gleason ≤ 6 prostate cancer opt for AS, the cost to the
Australian healthcare system will decrease to $58.051 million.
Very low rates of retention of men on AS will result in increased costs that would
approach those of Scenario 1 (in which AS was not used).
Protocols for following men on AS are varied and thus will have differing cost
implications. However, the cost of monitoring a patient on AS would have to increase by
four- to five-fold over that proposed in this analysis before the costs associated with AS
would equal those associated with immediate active treatment.
$4,262 more costly in May 2006 (date report published), inflated (using the RBA calculator at
http://www.rba.gov.au/calculator/ - accessed 27/10/2010) over 3.5 years at an average inflation rate of
2.9% gives a value of $4,717 in present day Australian dollars.
13
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Most importantly, whether men are able to avoid treatment altogether or merely delay it,
the time spent under AS, with proper reassurance, will represent time spent without the
potentially lifelong side effects of active treatment. This is supported by the cost–utility
analysis by Ollendorf et al (2009) in which the average patient under AS experienced 1.15
more QALYs than men who received immediate RP. This benefit is gained despite
Ollendorf’s model’s moving more than half of all men under AS into active treatment
over the duration of the model.
More accurate identification of men who are likely to require active treatment will
improve the retention of men on AS. This will allow men to avoid unnecessary
treatments and their related side effects, and will reduce the economic costs of treating
localised prostate cancer for both patients and the Australian healthcare system.
Other relevant considerations
Expert opinion
In July 2007, following an application to the Department of Health and Ageing from the
Australian and New Zealand Association of Urological Surgeons (ANZAUS), the
indications for MBS reimbursement of low-dose-rate brachytherapy (LDRBT) were
increased to include patients with Gleason 7 prostate cancer. As indicated earlier under
‘Intended Purpose’ on page 5, the treatment of men with Gleason 7 prostate cancer with
LDRBT alone appears to be at odds with many international guidelines.
Gleason score is a strong prognostic indicator for oncological and therefore overall
survival outcomes (Andren et al 2006), and it is well recognised that men with a Gleason
score of 7 but with a primary Gleason grade of 4 fare poorly compared with men who
have a primary Gleason grade of 3 (Burdick et al 2009; Chan et al 2000; Kang et al 2007;
Khoddami et al 2004; Lau et al 2001; Makarov et al 2002; Rasiah et al 2003; Stark et al
2009). One reason for this may be related to the differences in likelihood that cancer cells
have spread beyond the prostate. Partin et al (2001) reported that, among men with
Gleason scores of 7, those with a primary grade of 4 were found to have prostate cancer
beyond the prostate in 57% of cases.
This systematic review was planned with the aim of stratifying patient outcomes by
Gleason score—specifically into a Gleason ≤ 6 group, a Gleason 3+4=7 group and a
Gleason 4+3=7 group. Unfortunately, the overwhelming majority of papers included in
this review tended either to treat only low-risk patients (Gleason score ≤ 6) or not to
separate patients on the basis of Gleason score/grade. A proportion of papers that
included patients with a Gleason score of 7 were excluded because the patients had other
intermediate- or high-risk characteristics that rendered them ineligible.
The literature reports conflicting effects of primary Gleason grade among men with
Gleason score 7 on the outcomes of LDRBT. Potters et al (2003) and Burdick et al (2009)
found statistically inferior results among men with Gleason 4+3 compared with Gleason
3+4 scores, whereas Merrick et al (2007) did not show a difference. Munro et al (2010)
reported a greater proportion of Gleason 4+3 disease recurring by 8 years following
treatment but the trend was not statistically significant. Irrespective of whether Gleason
4+3 disease is the same or worse than Gleason 3+4 disease, it is not clear whether
treatment with surgery or EBRT results in better outcomes than LDRBT.
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Despite the lack of evidence found by this review, as well as in the additional searched
literature, to show a difference in outcomes between men with Gleason 3+4=7 and
Gleason 4+3=7 disease, the Advisory Panel has reservations about endorsing the use of
LDRBT for treating Gleason 4+3=7 prostate cancer. Given the high expected rate of
extracapsular extension among men with Gleason 4+3=7 disease, LDRBT, which has
limited extracapsular effect, may be a less suitable treatment option than either EBRT or
RP.
Site approval / accreditation
LDRBT, like EBRT, requires a purpose-built radiation treatment facility and a
multidisciplinary team of appropriately trained staff. Not unlike RP, the volume of
patients treated by an LDRBT team will be an important predictor of implant adequacy
and ultimate patient outcomes. Recognising that there is probably a learning curve
involved with the delivery of LDRBT (Acher et al 2006; Keyes et al 2006; Lee et al 2000;
Liu et al 2010; Tanaka et al 2009), adequate training and a continued minimum patient
throughput for an LDRBT team is essential to ensure the best possible outcomes of the
procedure. Defining the required standards of training and experience is the role of the
relevant professional bodies.
Access and equity
Public versus private sectors
Currently, about 70% of LDRBT procedures occur in the private healthcare sector.
Access to LDRBT in public hospitals is limited primarily due to the funding
arrangements for the BT seeds. While a number of public hospitals offer LDRBT, the
number of procedures they are able to perform is limited by the amount of funding they
receive from the state/territory governments. Given the likely small overall differences in
the costs of LDRBT, RP and EBRT, decisions to fund one treatment over another likely
represent efforts at limiting the cost implications for particular payers. The costs to the
state/territory governments will be approximately the same for men treated with LDRBT
and RP, but will be higher than treating men with EBRT (for which the MBS bears most
of the cost in both the public and private sectors).
The restriction on the number of LDRBT procedures in the public sector will mean that
some uninsured men will be unable to access their preferred choice of treatment or will
have to pay the full amount for treatment in the private sector.
Greater funding of the LDRBT procedure in the public sector will improve equity. This
may be particularly important for uninsured men in non-metropolitan areas who may
benefit from the shorter duration of treatment needed for LDRBT. In addition, LDRBT
teams in public hospitals will be exposed to a higher volume of procedures, which will
improve expertise and the overall quality and efficiency of the service. If greater access to
LDRBT in the public sector reduces the number of men opting for EBRT, there may be
a cost saving to the MBS that could be used to subsidise the cost of BT seeds in the
public sector.
The out-of-pocket expenses for patients undergoing LDRBT in the private sector are
currently substantial. If LDRBT becomes more available in the public sector, there is a
risk that patients who would have undergone LDRBT in the private sector would opt for
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treatment in the public sector. Therefore, judicious subsidy of BT seeds for private
patients may ensure that both public and private sectors can continue to offer LDRBT as
a treatment option for localised prostate cancer on a more equitable basis.
Rural versus metropolitan
Due to the requirement for a highly specialised team and an expensive purpose-built
facility, the provision of a LDRBT service outside of metropolitan areas is unlikely to be
clinically optimal or cost effective.
However, given the brevity of the treatment (typically 1–2 days), LDRBT for prostate
cancer represents an attractive alternative to EBRT (which is delivered in an outpatient
setting over 7–8 weeks) for patients who must travel from rural or remote areas for
treatment. In addition, because many of the services required for the preparation of the
treatment (staging, TRUS and urinary flow rate) may be available in larger regional
centres, the travel necessary for a rural patient may be limited to that required for the
procedure alone.
To facilitate access to LDRBT for men living in rural or remote areas, it is important that
adequate access to general practitioners is available to ensure that a diagnosis of prostate
cancer is made early and while radical treatment remains an option. There is some
evidence that Australian men residing in rural areas are less likely to access curative
treatments and more likely to die from prostate cancer than their metropolitan
counterparts ( Coory & Baade 2005; Hall et al 2005). Without access to high-quality
primary health care, the diagnosis of prostate cancer may be delayed until it is
symptomatic, at which time the disease may be too advanced for LDRBT. Support
through training and connections with specialist centres as well as incentives for general
practitioners may ensure early and adequate management of prostate cancer in men from
rural and regional areas. It is also important to provide access to an initial consultation
with a cancer specialist, either a urologist or radiation oncologist, who can assess the
patient and inform him of suitable treatment options for localised prostate cancer,
including LDRBT.
As LDRBT may require only a very brief stay in a metropolitan area, there may be a
substantial cost saving in subsidised travel and accommodation in comparison with
treatments of longer duration, such as EBRT, for men travelling from rural or remote
areas. Currently, all states and territories have patient accommodation and travel schemes
(information available at:
http://www.health.gov.au/internet/main/publishing.nsf/Content/health-roi-radiotherindex.htm#Accomodation)
LDRBT requires a follow-up scan at approximately 1 month to assess the adequacy of the
prostate implant. This process requires access to a CT scanner, after which the image is
assessed by a LDRBT expert who can reconstruct the distribution of dose throughout the
prostate by mapping the implanted seeds. Ideally, regional centres that can provide a CT
scan of the relevant region could be used, with the CT images sent electronically or copied
to a storage device, such as a compact disc, and posted to the LDRBT centre for postimplant dosimetric verification. Investment in technology and data linkage to enable
services like these to exist will be important for reducing the added burden of seeking
treatment for men in rural or remote areas.
Along with disease monitoring and the treatment of patient side effects, follow-up
schedules should be sensitive to the travel implications for rural or remote patients.
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Where possible, patients should be offered follow-up with specialists who visit regional
areas, or with general practitioners who are adequately trained and provided with
guidelines for ongoing prostate cancer monitoring.
For longer term follow-up, research into the effectiveness of internet or
telecommunication-based consultations would lessen the burden of travel for rural and
remote patients.
In conclusion, while developing radiation oncology services in areas with smaller
populations may not be logistically feasible, the following approaches will minimise the
disadvantages for men from rural or remote areas seeking treatment for prostate cancer:
 developing strong links between smaller centres that service rural and remote areas
and the radiation oncology services of metropolitan areas
 ensuring adequate prostate cancer specific training of and incentives for general
practitioners in rural and remote areas to facilitate the timely diagnosis of prostate
cancer and the monitoring of patients following prostate cancer treatment
 investment in technology that will improve the efficiency of managing patients, such as
linking CT scanners in regional areas with specialist centres and internet or
telecommunication for patient consultations when appropriate.
A trial offering radiotherapy in regional centres of Victoria was jointly run by the
Australian and Victorian governments between 2002 and 2007 (Australian Government
Department of Health and Ageing 2009a). The trial involved the operation of single
radiotherapy machines in regional Victoria to service the surrounding population. These
single machine units were operated as a spoke of larger central specialist radiation
oncology hubs. It was found that the cost of providing radiation oncology treatments in
Ballarat was similar to that in East Melbourne. However, the total cost to the patient or
carer represented an overall saving of at least $400,000. This approach requires careful
planning and, while not an option for all regional centres, it should be a consideration for
policy makers.
Patient journey
A diagnosis of cancer can be a frightening and uncertain period in a person’s life.
Different men will respond to the diagnosis of prostate cancer differently and each
experience will be unique. However, most patients who are diagnosed with localised
(confined to the prostate) low- to moderate-risk prostate cancer will choose one of four
paths—surgery, EBRT, LDRBT or AS (close monitoring with the intention to intervene
if the cancer shows signs of progressing).
While most men with low- to moderate-risk prostate cancer may be suitable for all four
management options, some patient characteristics may preclude some men from some
options. For example, other medical conditions may increase the risks associated with
surgery, or a very large prostate will make LDRBT difficult to perform. In addition,
changes in PSA level or concerning findings on biopsy may make AS a less safe option.
Figure 7 presents a typical journey for a man who is diagnosed with localised prostate
cancer.
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Figure 7
Patiert journey for a man diagnosed with localised prostate cancer
Brachytherapy for the treatment of prostate cancer- MSAC 1089.1
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
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Future research
The current systematic review is the third MSAC assessment of 125I LDRBT for localised
prostate cancer. Like many technologies, LDRBT has become an established treatment
despite a lack of evidence. Furthermore, there is little evidence to support the efficacy of
comparators within this review; therefore, a conclusion that LDRBT is as effective as
either RP or EBRT does not imply that LDRBT is a more effective treatment than no
treatment.
One randomised controlled trial comparing RP with watchful waiting showed an
increased overall and cancer-specific survival among men treated with RP (Bill-Axelson et
al 2008). The Scandinavian Prostate Cancer Group 4 (SPCG-4) trial showed a difference
in cancer-specific survival at 12 years of 5.4% [95% CI 0.2 to 11.1%]. This means that
nearly 19 men would have to be treated with RP to prevent one prostate cancer death at
12 years following treatment. Importantly, the effect of treatment on survival did not
extend to men diagnosed with prostate cancer over the age of 65 years and, given that
this population was largely unscreened, this may represent an even younger cut-off in
screened populations.
While it is almost certain that RP is effective in some patients, further clinical research of
all modalities of prostate cancer treatment could help to better inform both clinicians and
patients of the relative risks and benefits of each treatment choice. RP, EBRT and
LDRBT all carry risks of short- and long-term side effects, some of which will adversely
affect patient quality of life. Therefore, avoiding overtreatment of men who are not
destined to die of prostate cancer or experience prostate cancer related morbidity would
represent both an avoidance of treatment-related side effects for the patient and a
substantial cost saving to the healthcare system.
Trials (START14, PRIAS15, and ProtecT16) comparing AS with active treatments are
currently underway and may help to assess the risks and benefits of AS as a management
option for prostate cancer.
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Conclusions
Safety
The assessment of safety-related outcomes following low-dose-rate brachytherapy
(LDRBT) for localised prostate cancer involved one randomised controlled trial
comparing LDRBT with radical prostatectomy (RP) and 17 studies comparing LDRBT
with one or more of: external beam radiotherapy (EBRT), RP and active surveillance
(AS). The body of evidence for the safety of LDRBT differed between comparators and
has been presented in Table 24, Table 25 and Table 26 in the discussion of this report.
While most studies were judged to be of moderate quality, the overall evidence-base was
deemed satisfactory for comparisons with RP and poor for comparisons with EBRT and
AS. Consistency in studies comparing LDRBT with RP was generally good, although
comparisons with EBRT had some inconsistency. Only one study involved comparisons
with AS and therefore consistency is not applicable. Many of the differences between
LDRBT and RP were large and the clinical impact of the evidence was judged to be
substantial; however, as the differences between LDRBT and EBRT were smaller and, in
some cases, uncertain, the clinical impact of the evidence was deemed to be slight. Only
poor-quality evidence was available for comparisons with AS and treatment effect
differences are difficult to ascertain; therefore, the clinical impact was judged to be slight.
The evidence for all comparators was found to be generalisable and applicable to the
Australian population and healthcare setting.
Meaningful synthesis of results is marred by the large number of tools and methods used
to describe similar outcomes. For example, this review has reported on six different
questionnaires or clinician-reported scales, none of which are directly comparable.
Furthermore, questionnaire-related results are invariably reported as a mean, or a mean
change from baseline, across a group. Irrespective of whether there is a significant
difference between groups or not, it is impossible to determine what proportion of
subjects experienced a clinically meaningful event or change in quality of life (QoL).
Consequently, it may be possible to determine whether one treatment performs better or
worse than another but an effect size will be difficult to interpret if QoL within groups is
not normally distributed. In other words, if most patients experience minimal or clinically
insignificant changes, but a small proportion experience devastating changes, the overall
mean difference may be small and unrepresentative of the true clinical picture. This is not
likely to be an obscure or hypothetical situation. Common sense tells us that there will be
large differences in QoL following treatment in men who report serious radiation
proctitis or, more commonly, incontinence, compared with those who do not. The mean
QoL change for the whole group may be only small but, for the man who is in pain or
who is largely incontinent or requires invasive surgery, the change in QoL will be very
important.
Patients who receive either LDRBT or EBRT are likely to experience transient irritative
or obstructive symptoms. These may manifest as painful urination, increased daytime or
nocturnal frequency, haematuria or urge incontinence. For most men these symptoms
will abate within 6 months or 1 year following treatment; however, for some men
symptoms may persist longer. Irritative or obstructive symptoms are rare following RP
and were not assessed for AS.
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Urinary incontinence is common soon after RP and far less likely following either
LDRBT or EBRT. Most men regain continence following RP by 1 year; however, rates of
incontinence continue to be higher at 3 years following RP than either LDRBT or EBRT.
It is likely that LDRBT and EBRT may be associated with increased rates of incontinence
from baseline, although this may be a consequence of urgency due to bladder or urethral
irritation rather than lack of control. Incontinence appears uncommon in men managed
with AS.
Urinary function and bother, as measured by QoL instruments, slightly favoured
radiation treatments over RP, although the magnitude of the difference is uncertain and
probably small.
Patients who are treated with RP experience fewer bowel-related side effects, such as
frequency or changes to bowel habit, painful bowel movements, bleeding and
incontinence, than men who are treated with LDRBT. Men who are treated with LDRBT
may have fewer bowel-related side effects than men who are treated with EBRT.
Differences in bowel function and bother across treatments are likely to be large soon
after treatment and reduce over time. However, there may still be function- or botherrelated detriments at 3 years following treatment among men who receive EBRT. Bowel
bother appears uncommon in men managed with AS.
Erectile dysfunction in the community is common among men aged 60 years and older,
and increases with age. Differences in age and pre-treatment function of men opting for
treatments of localised prostate cancer, as well as the perceived effectiveness of treatment
regarding the preservation of erectile function, will seriously confound studies reporting
on erectile dysfunction following treatment. The use of medications or aids for erectile
dysfunction will also confound treatment effects if their use is disparate across groups.
Erectile dysfunction is far more common following RP than LDRBT, although there may
be little difference between LDRBT and EBRT. Differences in reported potency rates
across studies may reflect patient selection, treatment technique, surgeon experience or
access to rehabilitative treatments following treatment. Erectile dysfunction among men
managed with AS could not be assessed.
Overall health-related QoL may be transiently lower in patients following RP compared
with LDRBT and EBRT, perhaps reflecting transient high incontinence rates, although
this difference is small and does not endure beyond approximately 6 months. Given the
large number of treatment side effects that may contribute to reduced QoL in patients
following treatment for localised prostate cancer, overall health-related QoL may not be
an informative metric for either patients or clinicians. Because patients will have different
aversions to different treatment side effects, QoL will be maximised when an informed
patient considers the risks associated with each treatment and selects the treatment best
suited to himself.
Effectiveness
Primary effectiveness
The available evidence for the primary effectiveness of LDRBT for the treatment of lowrisk prostate cancer was of moderate quality overall. Results indicate that LDRBT
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effectiveness outcomes at less than 10 years are no different compared with RP and
EBRT. The highest quality cohort study reporting on all-cause survival (Zhou et al 2009)
found no difference between RP and LDRBT, while results for LDRBT and EBRT were
similar. Regardless of the potential for bias, the direction of the most important biases in
this study did not favour LDRBT, despite which its performance was still at least
comparable to other modalities. Indeed, the weight of evidence presented by Zhou and
colleagues (2009) provides reasonable certainty that LDRBT is no worse that RP or
EBRT. Randomised controlled trials are lacking (only one included study) due to patient
preferences and physician selection on the basis of side effect profiles, and Zhou et al
(2009) comprises the best available evidence. Evidence provided by the lower quality
studies (Pickles et al 2010; Vicini et al 2002) did not refute these results. The majority of
patients examined in these studies had localised prostate cancer and were generalisable to
the target population within Australia. However, an unknown proportion of LDRBT
patients studied by Zhou et al (2009) were likely to have been treated with palladium.
Consequently, the results are applicable to the Australian healthcare context only with
some reservations.
Secondary effectiveness
Studies that presented secondary effectiveness were all of moderate quality and the
majority (Beyer & Brachman 2000; Giberti et al 2009; Wong et al 2009) found no
differences in bNED for LDRBT, EBRT or RP. The randomised controlled trial by
Giberti et al (2009) presented 5-year bNED for low-risk prostate cancer patients
undergoing RP or LDRBT and found no difference between the two treatments. There
were some limitations in the statistical analysis and loss to follow-up was also a problem;
however, the direction and size of these potential effects on outcome cannot be known.
Giberti et al (2009) was the only level II study to address (secondary) effectiveness
outcomes and it is reasonable to conclude, on the basis of the results, that LDRBT for the
treatment of low-risk prostate cancer is probably no worse that EBRT in terms of bNED
at 5 years. Some evidence (Pickles et al 2010) suggested bNED may be 10% better among
LDRBT patients than EBRT patients but, given that three-quarters of the participants in
the EBRT arm received suboptimal dosage, these results need to be interpreted with
caution. The poor-quality study (Vicini et al 2002) gave no evidence of a valid statistical
comparison. Biochemical disease-free survival outcomes for all studies of
secondary effectiveness are likely to have been biased, but the extent of the bias is unable
to be quantified and its direction is unknown. As a consequence, the results are uncertain.
Economic considerations
The comparative effectiveness of LDRBT, RP, EBRT and AS for the treatment of
localised prostate cancer is not known and therefore a cost-effectiveness analysis could
not be performed.
Cost–utility analysis
Using the assumption of equal effectiveness regarding survival across treatments, a cost–
utility analysis from the US found that men treated with LDRBT for prostate cancer
retained more quality adjusted life years (QALYs) than men who received EBRT or RP.
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Men initially treated with AS experienced the largest number of QALYs. Costs were from
US sources and their generalisability to the Australian healthcare system is uncertain.
Financial impact analysis
The expected number of men who would be eligible for LDRBT is approximately 5,000
per year. The anticipated uptake of LDRBT is approximately 1,400 procedures in 2010,
although this is likely to increase.
For the financial impact analysis of LDRBT, two scenarios were costed. The first scenario
includes only the cost of active treatments (LDRBT, EBRT and RP) and follow-up over a
period of 10 years. The second scenario includes, in addition, the likely uptake of AS
among men diagnosed with Gleason ≤ 6 prostate cancer. This scenario reflects the best
estimate for the costs associated with the treatment of localised, low- to intermediate-risk
prostate cancer in Australia.
Scenario 1
The cost to the MBS of treating one-third of all potentially eligible men with LDRBT is
approximately $5.829 million per year. The overall annual cost to the MBS of treating all
5,000 men is estimated at $28.362 million. The cost of LDRBT to the MBS is
approximately $1.898 million greater than for RP, and $12.774 million less than for
EBRT. Therefore, the estimated financial impact of continued listing on the MBS for
LDRBT will depend on how many men select LDRBT instead of RP and LDRBT
instead of EBRT. However, LDRBT would have to draw almost seven times as many
men from RP than from EBRT to result in an increased net cost to the MBS.
The total cost to the Australian healthcare system for treating 5,000 men with LDRBT,
EBRT or RP is approximately $66.726 million per year. The per patient incremental costs
of LDRBT compared with EBRT and RP are small, and therefore the financial impact on
the Australian healthcare system of continued listing on the MBS for LDRBT will be
almost negligible.
Scenario 2
The utilisation of AS in Australia is unknown and a figure of 20% of men with Gleason
≤ 6 disease has been used for costing purposes. Assuming that 57% of men on AS will
eventually opt for active treatment, the discounted annual cost to the MBS of treating men
with LDRBT is approximately $5.590 million. The overall cost to the MBS of treating
men with LDRBT, EBRT, RP or AS is $28.934 million, a small increase from the overall
cost to the MBS of just treating men with LDRBT, EBRT or RP. However, the overall
annual cost to the Australian healthcare system of treating all 5,000 men with LDRBT,
EBRT, RP or AS is approximately $1.043 million less than in scenario 1
(without AS).
The cost of managing men with AS will depend upon the number of men who opt for
AS, the cost of the surveillance protocol, the number of men who eventually opt for
active treatment, and the treatment that they select. Greater use of AS and a lower
transition rate to treatment will ultimately result in a lower cost to the Australian
healthcare system.
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All treatments for prostate cancer may be accompanied by side effects; therefore,
avoiding or delaying treatment among men who do not immediately require it, as is
accomplished by AS, may have substantial benefits for quality of life.
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Appendix A
MSAC terms of reference
and membership
The Medical Services Advisory Committee (MSAC) is an independent scientific committee
comprising individuals with expertise in clinical medicine, health economics and consumer
matters. It advises the Minister for Health and Ageing on whether a new medical service should
be publicly funded based on an assessment of its comparative safety, effectiveness, costeffectiveness and total cost, using the best available evidence. In providing this advice, MSAC
may also take other relevant factors into account. This process ensures that Australians have
access to medical services that have been shown to be safe and clinically effective, as well as
representing value for money for the Australian healthcare system.
MSAC is to:


advise the Minister for Health and Ageing on medical services that involve new or emerging
technologies and procedures, in relation to:
o
the strength of evidence in relation to the comparative safety, effectiveness, costeffectiveness and total cost of the medical service;
o
whether public funding should be supported for the medical service and, if so, the
circumstances under which public funding should be supported;
o
the proposed Medicare Benefits Schedule (MBS) item descriptor and fee for the service
where funding through the MBS is supported;
o
the circumstances, where there is uncertainty in relation to the clinical or costeffectiveness of a service, under which interim public funding of a service should be
supported for a specified period, during which defined data collections under agreed
clinical protocols would be collected to inform a re-assessment of the service by MSAC
at the conclusion of that period;
o
other matters related to the public funding of health services referred by the Minister.
advise the Australian Health Minister’s Advisory Council (AHMAC) on health technology
assessments referred under AHMAC arrangements.
MSAC may also establish subcommittees to assist it to effectively undertake its role. MSAC may
delegate some of its functions to such subcommittees.
Page 110 of 261
Brachytherapy for the treatment of prostate cancer- MSAC 1089.1
The membership of MSAC at the December 2010 meeting comprised a mix of clinical expertise
covering pathology, nuclear medicine, surgery, specialist medicine and general practice, plus
clinical epidemiology and clinical trials, health economics, consumers, and health administration
and planning:
Member
Expertise or affiliation
Professor Robyn Ward (Chair)
Medical Oncology
Associate Professor Frederick Khafagi
(Deputy Chair)
Nuclear Medicine
Professor Jim Butler (Chair, Evaluation
Sub-committee)
Health Economics
Associate Professor John Atherton
Cardiology
Professor Justin Beilby
General Practice/Research
Associate Professor Michael Bilous
Anatomical Pathology
Professor Jim Bishop AO
Chief Medical Officer (ex-officio member)
Professor Peter Cameron
Trauma and Emergency Medicine
Associate Professor Kirsty Douglas
General Practice/Research
Professor Kwun Fong
Thoracic Medicine
Professor Richard Fox
Medical Oncology
Professor John Horvath
Renal Medicine/Health Workforce
Ms Elizabeth Koff
Health Administration
Professor Helen Lapsley
Health Economics
Professor Peter McCluskey
Ophthalmology
Mr Russell McGowan
Consumer Health Representative
Dr Allan McKenzie
Radiology
Dr Graeme Suthers
Genetics/Pathology
Mr David Swan
AHMAC Representative (ex-officio
member)
Professor Ken Thomson
Radiology
Dr Christine Tippett
Obstetrics/Gynaecology
Associate Professor David Winlaw
Paediatric Cardiothoracic Surgery
Dr Caroline Wright
Colorectal Cancer
Page 112 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Appendix B
Advisory Panel and
Evaluators
Advisory Panel – Application 1089.1 – Brachytherapy for the
treatment of prostate cancer
Member
Nomination / Expertise or Affiliation
Associate Professor Fred Khafagi (Chair)
Member of MSAC
Nuclear Medicine Physician
Dr Allan McKenzie (Deputy Chair)
Member of MSAC
Radiologist
Dr Ross Cartmill
Urologist
Professor Tony Costello
Urologist Prostate Specialist
Professor Gillian Duchesne
Radiation Oncologist Uro-Oncology
Mr Bill McHugh
Expert Consumer
Professor Anatoly Rozenfeld
Medical Radiation Physicist
Evaluation Sub-committee input
Name
Organisation
Professor Andrew Wilson
ESC member
Evaluators
Name
Organisation
Mr David Tamblyn
Adelaide Health Technology Assessment
Mr Ben Ellery
Adelaide Health Technology Assessment
Ms Tracy Merlin
Manager, Adelaide Health Technology
Assessment
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 113 of 261
Appendix C
Table 28
Search strategies
Additional sources of literature
Source
Location
Internet
Australian Clinical Trials Registry
http://www.actr.org.au
NHMRC- National Health and Medical Research Council (Australia)
http://www.health.gov.au/nhmrc/
US Department of Health and Human Services (reports and
publications)
http://www.os.dhhs.gov/
New York Academy of Medicine Grey Literature Report
http://www.nyam.org/library/greylit/index.s
html
Trip database
http://www.tripdatabase.com
Current Controlled Trials metaRegister
http://controlled-trials.com/
National Library of Medicine Health Services/Technology Assessment
Text
http://text.nlm.nih.gov/
U.K. National Research Register
http://www.update-software.com/National/
Google Scholar
http://scholar.google.com/
Hand searching (journals from 2009)
Acta Radiologica
Library or electronic access
BJU International
Library or electronic access
Brachytherapy
Library or electronic access
Cancer
Library or electronic access
Cancer Radiothérapie
Library or electronic access
European Urology
Library or electronic access
International Journal of Radiation Oncology, Biology and Physics
Library or electronic access
International Journal of Urology
Library or electronic access
Journal of Clinical Oncology
Library or electronic access
Journal of Urology
Library or electronic access
Radiotherapy and Oncology
Library or electronic access
Seminars in Radiation Oncology
Library or electronic access
Urology
Library or electronic access
Expert clinicians
Studies other than those found in regular searches
MSAC Advisory Panel
Pearling
All included articles will have their reference lists searched for
additional relevant source material
Page 114 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 29
Consumer and professional websites for additional information
Consumer websites
Andrology Australia
http://www.andrologyaustralia.org/
Lions Australia Prostate Cancer Website
http://www.prostatehealth.org.au/
Prostate Cancer Foundation of Australia
http://www.prostate.org.au/
Professional societies
American Urological Association
http://www.auanet.org/
Urological Society of Australia and New Zealand
http://www.urosoc.org.au/
Royal Australian and New Zealand College of Radiologists
http://www.ranzcr.edu.au/
Trans-Tasman Radiation Oncology Group
http://www.trog.com.au/
Medical Oncology Group of Australia
http://www.moga.org.au/
American Brachytherapy Society
http://www.americanbrachytherapy.org/
American Society for Radiation Oncology
http://www.astro.org/
Radiation Therapy Oncology Group
http://www.rtog.org/
European Association of Urological
http://www.uroweb.org/
European Society for Therapeutic Radiology and Oncology
http://www.estro.org/
European Org. for Research and Treatment of Cancer
http://www.eortc.be/
National Cancer Institute
http://www.cancer.gov/
National Cancer Institute of Canada Clinical Trials Group
http://www.ctg.queensu.ca/
Southwest Oncology Group
http://www.swog.org/
Eastern Cooperative Oncology Group
http://www.ecog.org/
Northern Central Cancer Treatment Group
http://ncctg.mayo.edu/
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 115 of 261
Table 30
Websites of health technology assessment agencies
AUSTRALIA
Australian Safety and Efficacy Register of New Interventional
Procedures – Surgical (ASERNIP-S)
Centre for Clinical Effectiveness, Monash University
Centre for Health Economics, Monash University
http://www.surgeons.org/Content/NavigationMen
u/Research/ASERNIPS/default.htm
http://www.mihsr.monash.org/cce/
http://www.buseco.monash.edu.au/centres/che/
AUSTRIA
Institute of Technology Assessment / HTA unit
http://www.oeaw.ac.at/ita
CANADA
Agence d‘Evaluation des Technologies et des Modes
d‘Intervention en Santé (AETMIS)
Alberta Institute of Health Economics (IHE)
The Canadian Agency for Drugs And Technologies in Health
(CADTH)
http://www.aetmis.gouv.qc.ca/site/home.phtml
http://www.ihe.ca/
http://www.cadth.ca/index.php/en/
Canadian Health Economics Research Association
(CHERA/ACRES) – Cabot database
Centre for Health Economics and Policy Analysis (CHEPA),
McMaster University
http://www.chera.ca
Centre for Health Services and Policy Research (CHSPR),
University of British Columbia
Health Utilities Index (HUI)
Institute for Clinical and Evaluative Studies (ICES)
Saskatchewan Health Quality Council (Canada)
http://www.chspr.ubc.ca
http://www.chepa.org
http://www.fhs.mcmaster.ca/hug/index.htm
http://www.ices.on.ca
http://www.hqc.sk.ca
DENMARK
Danish Centre for Evaluation and Health Technology
Assessment (DACEHTA)
Danish Institute for Health Services Research (DSI)
http://www.dsi.dk/frz_about.htm
FINLAND
Finnish Office for Health Technology Assessment (FINOHTA)
http://finohta.stakes.fi/EN/index.htm
http://www.sst.dk/english/dacehta.aspx?sc_lang=en
FRANCE
L‘Agence Nationale d‘Accréditation et d‘Evaluation en Santé
(ANAES)
http://www.anaes.fr/
GERMANY
German Institute for Medical Documentation and Information
(DIMDI) / HTA
Institute for Quality and Efficiency in Health Care (IQWiG)
http://www.dimdi.de/static/en/index.html
http://www.iqwig.de
THE NETHERLANDS
Health Council of the Netherlands Gezondheidsraad
Institute for Medical Technology Assessment (Netherlands)
http://www.gezondheidsraad.nl/en/
http://www.imta.nl/
NEW ZEALAND
New Zealand Health Technology Assessment (NZHTA)
http://nzhta.chmeds.ac.nz/
NORWAY
Norwegian Knowledge Centre for the Health Services
http://www.kunnskapssenteret.no
SPAIN
Agencia de Evaluación de Tecnologias Sanitarias, Instituto de http://www.isciii.es/
Salud ―Carlos III‖I/Health Technology Assessment Agency
(AETS)
Andalusian Agency for Health Technology Assessment (Spain) http://www.juntadeandalucia.es/
Catalan Agency for Health Technology Assessment (CAHTA)
http://www.gencat.cat
SWEDEN
Center for Medical Technology Assessment
Swedish Council on Technology Assessment in Health Care
(SBU)
Page 116 of 261
http://www.cmt.liu.se/?l=en&sc=true
http://www.sbu.se/en/
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
SWITZERLAND
Swiss Network on Health Technology Assessment (SNHTA)
UNITED KINGDOM
National Health Service Health Technology Assessment (UK) /
National Coordinating Centre for Health Technology
Assessment (NCCHTA)
NHS Quality Improvement Scotland
National Institute for Clinical Excellence (NICE)
The European Information Network on New and Changing
Health Technologies
University of York NHS Centre for Reviews and Dissemination
(NHS CRD)
UNITED STATES
Agency for Healthcare Research and Quality (AHRQ)
Harvard School of Public Health
Institute for Clinical and Economic Review (ICER)
Institute for Clinical Systems Improvement (ICSI)
Minnesota Department of Health (US)
National Information Centre of Health Services Research and
Health Care Technology (US)
Oregon Health Resources Commission (US)
Office of Technology Assessment Archive
U.S. Blue Cross/ Blue Shield Association Technology
Evaluation Center (Tec)
Veteran‘s Affairs Research and Development Technology
Assessment Program (US)
http://www.snhta.ch/
http://www.hta.ac.uk/
http://www.nhshealthquality.org/
http://www.nice.org.uk/
http://www.euroscan.bham.ac.uk/
http://www.york.ac.uk/inst/crd/
www.effectivehealthcare.ahrq.gov/
http://www.hsph.harvard.edu/
http://www.icer-review.org/
http://www.icsi.org
http://www.health.state.mn.us/htac/index.htm
http://www.nlm.nih.gov/hsrph.html
http://egov.oregon.gov/DAS/OHPPR/HRC/about_us.shtml
http://fas.org/ota
http://www.bcbs.com/blueresources/tec/
http://www.research.va.gov/default.cfm
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 117 of 261
Appendix D
Page 118 of 261
Table 31
Data tables for urinary side effects
Urinary side effects resulting from low-dose-rate brachytherapy, radical prostatectomy, external beam radiotherapy and active surveillance for the treatment
of localised prostate cancer
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Population
Urinary function
(Giberti et al 2009)
Randomised controlled trial
N: 100 RP patients and 100 LDRBT patients
Single centre, Italy
Level II interventional
evidence
Questionnaires were completed for 89 RP patients
and 85 LDRBT patients
Mean scores (p-value) from questionnaires at four time points (higher
scores indicate worse function/symptoms)
Downs and Black quality
score: 19/27
Exclusion criteria were in accordance with
American Brachytherapy Society
Accrual: May 1999 – October
2002
Overall quality assessment:
Moderate
RP
LDRBT
No. patients
100
100
Age, years
65.2
(57–74)
65.6
(56–74)
5.9
5.7
7.8
10.0)
7.5 (3.5–
(2.9–9.3)
Gleason
score
PSA, ng/mL
Values are mean (range) unless otherwise
indicated
Pre-treatment
6 months
1 year
5 years
4.9 (NS)*
15.2 (<0.01)
4.7 (NS)
10.1 (0.01)
4.7 (NS)
5.1 (NS)
17.0 (<0.01)
36.0 (<0.01)
10.0 (NS)
15.0 (<0.01)
10.0 (NS)
17.0 (NS)
IPSS:
RP
LDRBT
4.6
4.9
EORTC-QLQ-PR25:
Urinary symptoms
RP
LDRBT
9.0
8.0
* p-values for change from pre-treatment value
Loss to follow-up is not reported.
Percentage of patients reporting urinary symptoms
6 months
1 year
Overall
13.0
NR
NR
NR
NR
NR
5.4
NR
NR
NR
NR
NR
NR
NR
6.5
Mild urinary
incontinence:
RP
LDRBT
Severe urinary
incontinence:
RP
LDRBT
Urethral stricture:
RP
Study
Study design and quality
appraisal
Population
Urinary function
LDRBT
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
NR
NR
2.0
NR
80.0
NR
20.0
5.0
NR
NR
NR
NR
NR
10.0
NR
EBRT
LDRBT
p-value
(n=216)
(n=158)
15.0 (6.9)
3.0 (1.4)
42.0 (26.6)
6.0 (3.8)
<0.001
0.176
3.5
0.5
19.2
5.6
<0.001
0.006
0
11 (7)
NR
Irritation:
RP
LDRBT
Urinary retention:
RP
LDRBT
(Eade et al 2008)
Prospective cohort
Single centre, US
Level III-2 interventional
evidence
N: 374 low-risk prostate cancer patients (as defined
by American Joint Committee on Cancer) with
Gleason score < 7
Downs and Black quality
score: 19/27
EBRT
LDRBT
n
216
158
Overall quality assessment:
Moderate
Age,
years
67.6 (27–81)*
64.7 (42–78)
PSA, ng/mL
5.2 (0.4–9.6)
5.2 (0.5–9.8)
BT patients:
May 1998 – August 2004
EBRT patients:
August 2001 – June 2004
* Values are median (range).
No patients were lost to follow-up.
Urinary outcomes, RTOG scale
Acute side effects:
GU* ≥ grade 2
GU grade 3
Late side effects:†
GU ≥ grade 2
GU grade 3
Urethral
stricture
* GU = genitourinary
† 3-year actuarial risk
Values are number (%) or % unless otherwise noted.
(Wong et al 2009)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: May 1993 – July
2004
Downs and Black quality
score: 19/27
Page 119 of 261
Overall quality assessment:
Moderate
N:853 consecutive patients with localised prostate
cancer*
Maximum achieved RTOG acute genitourinary side effects (< 3 months
following treatment)
LDRBT
n
GRADE (%)
225
Clinical stage:
T1
T2
197 (88)
28 (12)
PSA ≤10, ng/mL
193 (86)
Gleason score ≤ 6
173 (77)
0
1
2+*
p (chi-square)
Grade 3
3D-CRT (%)
38
22
40
<0.0001
1
IMRT (%)
27
22
52
3
LDRBT (%)
11
14
74
6
Maximum achieved RTOG late genitourinary side effects (> 3 months
Study
Study design and quality
appraisal
Population
Urinary function
following treatment)
Page 120 of 261
Adjuvant hormone
treatment
153 (68)
GRADE (%)
Low-risk:
158 (70)
0
1
2+*
p (chi-square)
grade 3
3D-CRT (%)
66
13
21
<0.0001
5
IMRT (%)
47
22
32
5
23
14
63
18
3D-CRT IMRT
n
270
314
LDRBT (%)
120 (44)
123 (46)
231 (74)
69 (22)
* Grade 3 side effects are combined with grade 2 to prevent small numbers
in cells for chi-square test.
PSA ≤, ng/mL 192 (71)
238 (76)
Clinical stage:
T1
T2
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Adjuvant
hormone
treatment
47 (17)
114 (36)
Low-risk
119 (44)
109 (35)
Importantly, grade 3 late side effects were 18% among LDRBT men
compared to 5% among both 3D-CRT and IMRT men. Treatment for urethral
stricture among 3D-CRT and IMRT patients occurred in about 2% of cases,
compared with 14% of cases among LDRBT patients.
Loss to follow-up: none evident.
Values are n (%).
* See study profile for further details.
(Buron et al 2007)
Prospective cohort
Multicentre, France
Level III-2 interventional
evidence
N: 435 men with low-risk prostate cancer from 11
French hospitals treated with LDRBT (308) or RP
(127)
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
Accrual:
March 2001 – June 2002
RP
LDRBT
Age (years)
62.7±6
65.2±6.3
Neoadjuvant
hormones (%)
6.3
43.5
IPSS
7.8
5.9
Loss to follow-up after 24 months was between
35% and 59% (n data not provided) depending on
treatment arm—see study profile for further details.
Values are mean±standard deviation, unless
otherwise specified.
Urinary outcomes, EORTC QLQ-PR25
RP
LDRBT
(n=127)
(n=308)
68.4
49.0
12.7
19.7
31.4
26.5
63.9
37.9
18.4
63.7
Urinary incontinence worse
than baseline, %:
Immediately post-treatment
24 months
Urinary urgency worse than
baseline, %:
2 months
24 months
Urinary pain worse than
baseline, %:
2 months
Study
Study design and quality
appraisal
Population
Urinary function
24 months
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
2.1
19.0
34.9
16.3
66.0
36.8
34.4
14.3
62.8
30.8
Increased diurnal urination, %:
2 months
24 months
Increased nocturnal urination, %:
2 months
24 months
Note: p-values not provided; main in-text data summarised as no other exact
values could be determined from the graphical presentation of results.
(Ferrer et al 2008)
Prospective cohort
Multicentre, Spain
Level III-2 interventional
evidence
Accrual: April 2003 – March
2005
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 841 organ-confined prostate cancer patients
RP
Age,
years
PSA,
ng/mL
64±5.5
7.9±3.3
Gleason
score 6.8±6.2
EBRT
69.2±5.5
LDRBT
66.9±6.5
10.1±7.9
6.9±2.3
6±1.1
5.7±4.4
Values are mean±standard deviation.
Mean±SD prostate specific HRQoL (urinary) scores at 2-year follow-up
for low-risk patients by treatment group
RP
EBRT
LDRBT
AUA-7†
5.9±6.2
5.38±5.2
5.83±5.3
EPIC urinary:*
87.7±13.8
94±11.2
91.9±11.6
Urinary
irritative
96.4±10.3
94.8±10.1
92.7±10.8
Urinary
incontinence
78.3±23.1
93.2±13.9
92.7±15.2
Loss to follow-up:
614 patients treated with LDRBT (275), RP (134)
and EBRT (205) were included in HRQoL analysis.
p-values for one-way comparison of HRQoL scores:
Page 121 of 261
RP vs EBRT
RP vs LDRBT
LDRBT vs EBRT
AUA-7
NS
NS
NS
EPIC urinary:
<0.001
<0.001
NS
Urinary
irritative
NS
0.005
NS
Urinary
incontinence
<0.001
<0.001
NS
† AUA-7 (American Urological Association Symptom Index) assesses
obstructive symptoms and ranges from 0 to 35, with higher scores indicating
worse function/symptoms.
Study
Study design and quality
appraisal
Population
Urinary function
Page 122 of 261
* All EPIC items were answered on a 5-point Likert scale and transformed
linearly to a scale of 0–100, with higher scores indicating better HRQoL.
(Hashine et al 2008)
Prospective cohort
Single centre, Japan
Level III-2 interventional
evidence
Accrual: January 2003 – July
2005
N: 213 (131 RP and 82 LDRBT patients)
RP
LDRBT p-value
Downs and Black quality
score: 17/27
Age, years*
(range)
68.0
70.5
0.016
(42–78) (50–85)
Overall quality assessment:
Moderate
PSA, ng/mL*
9.6
6.7
Gleason score, n
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
5–6
7
8–10
<0.001
<0.001
44
42
36
51
27
4
Neoadjuvant
hormones
8
18
Nerve-sparing
22
-
EBRT
-
1
UCLA-PCI scores (mean±SD)*
RP
LDRBT
p-value†
88.9±19.4
45.2±28.6
60.2±27.5
69.7±27.0
74.6±24.7
94.1±13.9
89.7±16.7
89.9±18.5
92.4±16.3
94.4±12.7
0.027
<0.001
<0.001
<0.001
<0.001
85.4±22.6
59.3±31.5
72.7±28.4
80.4±26.0
84.8±22.5
89.8±20.9
78.1±29.2
75.0±28.5
84.8±22.5
90.0±21.0
0.075
<0.001
0.585
0.441
0.041
Urinary function:
baseline
1 month
3 months
6 months
12 months
Urinary bother:
0.002
baseline
1 month
3 months
6 months
12 months
* All UCLA-PCI scores were transformed to a scale of 0–100, with higher
scores representing better HRQoL.
* Values are median.
† Mann-Whitney U test
(Pickles et al 2010)
Retrospective cohort
Multicentre, Canada
Level III-2 interventional
evidence
Accrual: July 1998 – January
2001
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 278 (139 LDRBT, 139 matched EBRT)
Side effects and catheter use
LDRBT EBRT
Age, years
64
71
PSA, ng/mL
5.6
6.4
Gleason score, %:
87.8
12.2
87.8
12.2
ADT use, %
31.7
30.2
Radiation
dose, Gy
144
68
≤6
7
Patients requiring
catheterisation
LDRBT
EBRT p-value
15
0
52
42
NA†
NA
2.9
0.7
Patients with catheter
removed after:
less than 1 week
more than 1 month
Acute grade 3
GU side effects
Prevalence of late
<0.001
Study
Study design and quality
appraisal
Population
Urinary function
Values are median unless otherwise specified.
grade 2 GU side effects:*
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
2 years
3 years
4 years
5 years
Overall
13–14
11–12
7
6–7
NR‡
3–4
5–6
2–3
0
NR
<0.001
Values are % or p-values as indicated.
* Data are estimates from graphical presentation of results in study.
† Not applicable
‡ Although percentages were not reported, it was stated that genito-urinary
(GU) side effects were greater for LDRBT than for EBRT; the p-value is
reported accordingly.
(Smith et al 2010)
Prospective cohort
Population-based, NSW,
Australia
Level III-2 interventional
evidence
Accrual: October 2000 – May
2003
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 4542 men (31,95 with histologically confirmed
T1a–2c prostate cancer and 1,347 controls with no
diagnosis of prostate cancer, as indicated and
cross-checked by registry data)
Baseline
3 years
AS
85.7±19.7
91.6±14.7
Nerve-sparing
RP
95.6±10.7
85.5±17.0
Controls, n
Non-nervesparing RP
94.2±12.4
83.3±19.2
92.9±13.8
92.6±15.2
All potential participants had to be physically and
mentally capable of a 30-minute telephone
interview in English.
Cases, n
Unadjusted mean urinary function (score range 0–100; higher scores
indicate better function)
Page 123 of 261
Potentially
eligible
3,195
1,347
EBRT
Final analysis
1,636
495
AS
200
NA
Combined
EBRT/ADT
90.7±15.1
89.9±16.5
RP
981
NA
LDRBT
96.8±7.2
93.5±14.3
EBRT
123
NA
Controls
95.2±11.8
95.4
Combined
EBRT/ADT
166
NA
LDRBT
58
NA
Mean age,
years
[95% CI]
61.2
61.2
[60.7, 61.7]
[61, 61.5]
Unadjusted mean urinary bother (score range 0–100; higher scores
indicate better function)
Baseline
3 years
AS
58.3±36.4
84.1±14.7
Nerve-sparing
RP
80.5±28.5
84.8±23.5
Non-nerve-
Study
Study design and quality
appraisal
Population
Urinary function
Page 124 of 261
sparing RP
80.6±28.6
83.1±25.3
EBRT
77.2±30.2
81.4±27.6
Combined
EBRT/ADT
69.9±35.3
79.3±28.5
LDRBT
80.6±26.9
84.4±24.6
Controls
89.2±22.6
89.7
Urinary incontinence, n (%)
Baseline
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Frank et al 2007)
Retrospective cohort
N: 960 men treated with LDRBT (160), RP (400)
and HDR EBRT (400)
Radiation oncology
department, US
Level III-2 interventional
evidence
Accrual: 1998–2000
Downs and Black quality
score: 16/27
Age, years
Overall quality assessment:
Moderate
Loss to follow-up:
625/960 (65%) in total completed a survey, of
whom 443 were found to have undergone
monotherapy and so were included in the
analysis—see study profile for further details.
LDRBT RP
EBRT
64
68
61
Values are median.
3 years
AS
12 (6.0)
6 (3.4)
RP
11.1 (1.1)
111 (12.3)
EBRT
0 (0.0)
3 (2.7)
Combined
EBRT/ADT
5 (3.0)
6 (3.9)
LDRBT
0 (0.0)
3 (7.0)
Controls
5 (1.0)
NA†
† Controls were not asked the relevant questions at year 3.
EPIC domain specific prostate cancer HRQoL scores† (mean±SD) [95%
CI]
LDRBT
EBRT
RP
Urinary
function
85.8±24.3
[80.1,91.4]
90.1±15.3
[87.5,92.7]
83.7±15.8
[81.7,85.7]
Urinary
bother
78±19.6
[73.5,82.6]
80.4±18
[77.4,83.5]
83.2 ±16.1
[81.1,85.3]
Incontinence
85.9±23
[80.6,91.2]
85.5±18.9
[82.3,88.7]
73.4±25.1
[70.2,76.6]
Irritation
79.6±19
[75.2,84]
85.2±12.8
[83,87.4]
88.2±11
[88.4,91.4]
No statistical difference in urinary function observed between LDRBT and
EBRT or RP (p=0.38 and 0.09 respectively).
No statistical difference in urinary bother between LDRBT and EBRT of RP
(p-values not specified).
Study
Study design and quality
appraisal
Population
Urinary function
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
RP patients had significantly worse urinary incontinence than LDRBT
patients (p<0.001), while no difference observed between LDRBT and EBRT.
LDRBT caused significantly more urinary irritation than RP (p<0.001) and
EBRT (p<0.01).
† Higher scores indicate better HRQoL outcomes (scale 0–100).
(Guedea et al 2009)
Prospective cohort
Single centre, Spain
Level III-2 interventional
evidence
April 2003 – March 2005
Downs and Black quality
score: 16/27
Overall quality assessment:
Moderate
N: 304 men with prostate cancer
Baseline EPIC scores†, mean±SD
LDRBT RP
n
56
114
143
Age, years
67.5
63.9
68.8
PSA, ng/mL
6.4
7.9
11.9
Gleason score
5.7
6.3
6.4
Values are mean and n as indicated.
RP
EBRT
LDRBT
Urinary irritation/
obstruction
94.6±9.4
96±7.7
95.2±8.8
Urinary incontinence
96.1±12.3
95.5±11.3
98.5±6.5
EBRT
(no statistical difference between baseline scores)
Change in EPIC score at 2 years post treatment, mean±SD
RP
EBRT
LDRBT
Urinary irritation/
obstruction
0.01±14.6
–2.5±13.0
–7.9±21.5
Urinary incontinence
–26.9±30.9
–3.9±16.2
–12.4±22.1
Comparison of EPIC scores by treatment after 2 years
Urinary irritation/
obstruction, p-value
Urinary incontinence,
p-value
LDRBT vs RP
<0.001
<0.05
RP vs EBRT
NR
<0.05
LDRBT vs EBRT
NR
NR
All groups§
<0.001
Page 125 of 261
§ ANOVA
Change in EPIC score at 2 years post treatment, multivariate
generalised estimating equation (GEE) model‡, mean±SD
RP
EBRT
LDRBT
Study
Study design and quality
appraisal
Population
Urinary function
Page 126 of 261
Irritative/obstructive
4.76±2.11
1.51±2.09
(reference)
Urinary incontinence
–11.45±4.02
2.37±3.86
(reference)
Comparison of EPIC treatment scores after 2 years, GEE model
Urinary irritation/
obstruction, p-value
Urinary incontinence,
p-value
LDRBT vs RP
0.025
0.005
RP vs EBRT
NR
NR
LDRBT vs EBRT
NR
NR
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
† EPIC scores range 0–100, with higher scores indicating better HRQoL.
‡ Adjusting for age, baseline scores, risk group and hormonal treatment, at
2 years post treatment.
Values are mean±SD unless otherwise indicated.
(Wei et al 2002)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: June 1995 – May
1999
N: 1,014 including 142 male controls who are not
further considered‡
LDRBT
EPIC* urinary scores for follow-up exceeding 1 year
LDRBT
EBRT
RP
Urinary irritative
Downs and Black quality
score: 16/27
n
112
Age, years
67.2±7.3
Overall quality assessment:
Moderate
Time since
primary therapy,
months
71.5†# [67.4,75.5]
84.2†‡ [81.2,87.2]
89.6#‡ [88.3,91.1]
92.8† [87.1,98.5]
77.5† [75,80.1]
Urinary incontinence
82.1 [74.4,89.9]
* Expanded Prostate Cancer Index, values are mean [99% CI].
21
Multivariable modelling was used to adjust for age, time since therapy,
Gleason score, clinical stage, PSA and use of hormonal therapy.
Adjuvant/
neoadjuvant
therapy, %
51
PSA, ng/mL
9.7±14.9
Gleason score, %:
2–6
7
8–10
68.3
23.2
8.5
EBRT
RP
† # ‡ Values that share a common symbol were significantly different in a
pairwise comparison (significance set at 0.008 after Tukey adjustment for
comparisons between three groups), p<0.0005.
Study
Study design and quality
appraisal
Population
Urinary function
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
n
203
896
Age, years
70.9±7.2
63.5±7.8
Time since
primary therapy,
months
29
30
Adjuvant/
neoadjuvant
therapy, %
33
28
PSA, ng/mL
9.1±12.7
7.3±7.2
Gleason score, %:
2–6
7
8–10
43.1
47.9
9.0
59.6
37.3
3.1
Values are median±SD, except where indicated.
‡ A control group used in the primary analysis was
not considered given that a secondary analysis
made direct comparison between treatment
modalities, in accordance with inclusion criteria for
this assessment.
Page 127 of 261
Prospective cohort
N: 94 (33 LDRBT, 61 RP patients)
Level III-2 interventional
evidence
BT
RP
p (chi-square)*
Single institution, Germany
Age, years (range)†
64 (54–75)
LUTS
88
80
0.352
Accrual: January 1999 –
December 2002
Downs and Black quality
score: 15/27
PSA, ng/mL†
9.2 (1.6–55.6)
Bothersome LUTS
30
11
0.024
Overall quality assessment:
Poor
Urgency
88
64
0.013
Gleason score†
5 (3–8)
Bothersome urgency
21
2
0.001
OCO*
0.78 (0.08–2.67)
Incontinence
52
66
0.183
Max flow < 10 mL/s, %
30
Bothersome incontinence
24
11
0.183
Residual vol > 50 mL, %
34#
Stress incontinence
18
53
0.001
Max capacity < 200 mL, %
15
Bothersome stress incont.
-
11
-
Have to wear pads
10
41
0.001
Have to wear >2 pads / day
0
6
0.133
(Kirschner-Hermanns et al
2008)
Urinary symptoms after 1 year, percentage of patients
RP
LDRBT
Study
Study design and quality
appraisal
Population
Urinary function
Page 128 of 261
Age, years (range)†
67 (57–75)
PSA, ng/mL†
7.7 (3.2–17.0)
Gleason score†
5 (2–7)
OCO*
0.74 (0.34–1.70)
Max flow < 10 mL/s, %
21
Residual vol > 50 mL, %
12#
Max capacity < 200 mL, %
6
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
† Median (range)
* Obstruction coefficient
# Chi-square, p=0.019 (RP cf LDRBT)
(Pinkawa et al 2009)
Single centre, Germany
Accrual: 2003–06
Comparison of two matched
single arms
N: 104 (52 in each group)
LDRBT
EBRT
Level III-3 interventional
evidence
Age, years
(range)
68 (51–77)
68 (48–77)
Downs and Black quality
score: 16/27
PSA, ng/mL
7 (1.5–14)
8 (2.5–24)
EBRT
Gleason score
< 7, n (%)
50 (96)
39 (75)
LDRBT
Neoadjuvant
hormones, n (%) 14 (27)
14 (27)
Overall quality assessment:
Moderate
Mean (quartiles) function and bother scores from the EPIC
questionnaire†
Time A§
Time B
Time C
83‡
(68;89;96)
90
(86;93;100)
65
(47;64;86)
57
(37;61;71)
88
(83;93;96)
82
(68;89;100)
94
(100;100;100)
97
(100;100;100)
80
(75;100;100)
71
(25;100;100)
92
(100;100;100)
86
(94;100;100)
82
(79;87;95)
90
(85;95;100)
64
(46;63;80)
57
(41;58;70)
87
(80;90;100)
82
(66;87;100)
Urinary bother:
Values are median (range) unless otherwise
specified.
Urinary
incontinence bother:
EBRT
LDRBT
Urinary obstructive/
irritative bother:
EBRT
LDRBT
§ Time A = before LDRBT/EBRT, Time B = 1 month after LDRBT / on the
last day of EBRT, Time C = median 16 months after LDRBT/EBRT.
Study
Study design and quality
appraisal
Population
Urinary function
‡ Italics indicate significant differences between treatment groups.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Quartiles = 25th, 50th, 75th percentiles.
Comparison of function and bother scores from the EPIC questionnaire
Time A vs B, p-value
Time A vs C, p-value
<0.01
<0.01
<0.05
<0.01
<0.01
<0.01
NS
<0.01
<0.01
<0.01
NS
<0.01
Urinary bother:
EBRT
LDRBT
Urinary
incontinence bother:
EBRT
LDRBT
Urinary obstructive/
irritative bother:
EBRT
LDRBT
Selected symptoms from the EPIC questionnaire
Page 129 of 261
Time A (%)
Time B (%)
Time C (%)
6
0
4†
17
4
10
4
2
16
28
6
12
2
2
26
37
0†
10
≥ 1 pad to control
urinary leakage:
EBRT
LDRBT
Moderate/big problem
from dripping/
leaking urine:
EBRT
LDRBT
Moderate/big problem
from pain on urination:
EBRT
LDRBT
† p<0.05 (responses in EBRT group are significantly different than in the
Study
Study design and quality
appraisal
Population
Urinary function
LDRBT group).
Page 130 of 261
† EPIC scale 0 to 100, with higher scores indicating better HRQoL.
(Bucci et al 2002)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Level IV interventional
evidence
N: 282
Age, years
Median (range) = 66 (38–78)
NHMRC case series quality
score: 6/6
Clinical stage
T1c–T2b
Overall quality assessment:
Good
Gleason score
≤ 7 (3+4 only)
(Crook et al 2008)
Case series
PSA, ng/mL, %:
≤ 10
82%
10 – ≤ 15
12%
N: 484
Single centre, Canada
Level IV interventional
evidence
Age, years
Mean (SD) = 63.1 (6.9)
NHMRC case series quality
score: 6/6
Clinical stage
T1c–T2a
Overall quality assessment:
Good
Gleason score
≤6
Accrual: March 1999 – July
2005
Case series
(Sacco et al 2003)
Case series
Single centre, Israel
Level IV interventional
evidence
Accrual: September 1996 –
October 2001
NHMRC case series quality
score: 6/6
Overall quality assessment:
Good
Catheterisation rate following LDRBT = 15% (n=43)
Median duration of catheterisation = 21 days (1–365)
Higher IPSS at baseline were associated with higher rates of catheterisation.
An increase in IPSS (scale 0–35) of more than 5 points to a total score of
more than 15 points was reported in 23%. Of those with raised IPSS, 30%
remained raised for more than 6 months.
Some urgency or urge incontinence was diagnosed in 6.4% of men; 3.9%
required medication for urgency or urge incontinence. In those whose
symptoms resolved, median duration was 12 months; 0.8% of men had
ongoing symptoms at the end of the study.
PSA
≤ 10 ng/mL
13 men (2.7%) required catheterisation after 1 year following treatment; 8 of
18 men required catheterisation due to urethral stricture.
N: 400 consecutive patients with early stage
prostate cancer
Number of patients who developed acute urinary retention requiring
catheterisation: 45 (11.3%)
Age, years
Median (range) = 65 (41–70)
Median number of days to development of acute urinary retention requiring
catheterisation: 12
Clinical stage
T1c: 73%, > T2a: 27%
Median (range) duration of catheterisation, days: 14 (1–365)
Gleason score
98% of patients ≤ 7
PSA
91% of patients ≤ 10 ng/mL
Loss to follow-up:
3 patients
Proportion of patients with acute urinary retention among those who did and
did not use corticosteroids (dexamethasone): 8.2% vs 18.8%, respectively,
p=0.006
Number of patients with gross haematuria: 2
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Population
Urinary function
(Keyes et al 2009)
Case series
N: 712 eligible from 932 consecutive patients
Multicentre, Canada
Case series
Accrual: July 1998 – June
2003
Level IV interventional
evidence
Age, years
Median (range) = 65.5 (46–82)
An increase in IPSS (scale 0–35) of more than 5 points greater than posttreatment nadir was reported in 53.2%; 66% of IPSS flare had resolved in
6 months, 90% had resolved in 1 year.
Clinical stage
<T2c
Note: overlapping population with Bucci 2002 (above)—different outcomes
reported
NHMRC case series quality
score: 5/6
Overall quality assessment:
Good
Gleason score
≤7
PSA, ng/mL, %:
≤ 10
85.8%
10 – ≤ 15
14.2%
Follow-up at least 34 months:
144 excluded due to living in remote area, 35 less
than 34 months follow-up, 41 with insufficient data.
(Mabjeesh et al 2007)
Single centre, Israel
Accrual: June 1998 – June
2006
Case series
N: 655
Number of patients with urinary retention requiring catheterisation: 21
Level IV interventional
evidence
Age, years
Mean±SD = 67.3±6.5
Median (range) days to onset of urinary retention requiring catheterisation: 1
(1–60)
NHMRC case series quality
score: 5/6
Clinical stage
T1 – T2c
Median duration of catheterisation, months (range): 6.25 (2–24)
Overall quality assessment:
Good
Gleason score
99.9% of patients ≤ 7
(Matzkin et al 2003)
Case series
Single centre, Israel
Level IV interventional
evidence
Accrual: not reported
NHMRC case series quality
score: 5/6
Page 131 of 261
Overall quality assessment:
Good
PSA
Mean±SD = 7.75±3.45 ng/mL
Loss to follow-up:
None apparent
N:300
Group 1: 136 preplanned
Group 2: 164 intraoperatively planned
Age, years:
G1: Mean 67.2
G2: Mean 68.4
Clinical stage
≤ T2
Gleason score
≤6
Number of patients with urethral stricture: 1
No patient experienced urinary incontinence following implantation.
Five patients experienced ‗prolonged‘ urinary retention, with three requiring a
transurethral resection of the prostate.
For the pre-planned group, IPSS returned to normal (±1 point) for 92% of
men by 12 months following treatment.
For the intra-operatively planned group, IPSS returned to normal for 95% of
men by 18 months.
Study
Study design and quality
appraisal
Population
Urinary function
Page 132 of 261
PSA, ng/mL:
G1: Mean 8.69
G2: Mean 7.95
(Mitchell et al 2008)
Case series
N: 1,535 men treated with permanent seed BT
Multicentre, UK
Level IV interventional
evidence
Age, years, median (range):
Centre 1: 63 (43–79)
Centre 2: 65 (40–79)
Centre 3: 63 (43–82)
Accrual: January 2003 –
October 2006
NHMRC case series quality
score: 5/6
Overall quality assessment:
Good
Clinical stage
T1c–T3a
Median IPSS* for patients at all centres increased from a baseline value of 5,
peaked at 18 after 6 weeks, and was not significantly different from baseline
at 12 months.
Median duration of catheterisation was 53, 18 and 53 days at centres 1, 2
and 3 respectively.
Urethral stricture rates were 1% at all centres.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Gleason score
> 97% of patients ≤ 7
* International Prostate Symptom Score, scale = 0–35
PSA
≤ 7 ng/mL
(Stone et al 2010)
Case series
Loss to follow-up:
NA, complete reporting for all patients registered on
database
N: 395
Single centre, US
Level IV interventional
evidence
Age, years
Mean 68.9 (SD±6.8)
NHMRC case series quality
score: 5/6
Clinical stage
T1b–T3a
Overall quality assessment:
Good
Gleason score
≤7
98.2%
Accrual: 1990 –2006
PSA, ng/mL:
≤ 10
10 – ≤ 20
> 20
9.3% of men suffered urinary retention following 125I LDRBT (n=31) lasting a
median of 42 days.
83.3%
14.4%
2.3%
Prostate volume > 50 cc
85% of men were treated with 125I LDRBT.
(Zelefsky et al 2007a)
Case series
N:562
Single centre, US
Level IV interventional
evidence
Age
Not reported
NHMRC case series quality
Clinical stage
Accrual: January 1998 –
December 2004
NCI CTCAE urinary side effects:
late grade 2
late grade 3
17%
3%
Study
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study design and quality
appraisal
score: 5/6
Population
Urinary function
99.8% ≤ T2
Overall quality assessment:
Good
Gleason score
99.8% ≤ 7
NCI CTCAE = National Cancer Institute Common Terminology Criteria for
Adverse Events
PSA, ng/mL, %:
≤ 10
94.5%
10 – ≤ 20
5.3%
> 20
0.2%
(Kao et al 2008)
Case series
N: 643 men with localised prostate cancer
Single centre, US
Level IV interventional
evidence
Age
Not reported
NHMRC case series quality
score: 4/6
Overall quality assessment:
Moderate
Clinical stage
T1a–T2c
Accrual: June 1995 –
February 2005
Gleason score
98.8% of patients ≤ 7
Median IPSS* increased from a baseline value of 6, peaked at 18 after
6 months and was not significantly different from baseline at 12 months.
Acute urinary retention occurred in 12.4% of patients.
Patient reported urinary QoL was unchanged before and after implantation.
* International Prostate Symptom Score, scale = 0–35
PSA
Median = 6.1 ng/mL
(Eckman et al 2010)
Case series
Loss to follow-up:
Urinary outcomes were available for 249 patients.
N: 394
Single centre, US
Level IV interventional
evidence
Age, years
Mean 67.3 (SD±7.6)
NHMRC case series quality
score: 3/6
Clinical stage
99.5% < T3
Overall quality assessment:
Moderate
Gleason score
95.7% < 8
Accrual: 1995–2007
In men who received LDRBT between 1993 and 1997, catheterisation for
urinary retention was 10%. Following 1997, catheterisation rates dropped to
2%. Following 1997, dexamethasone (6 mg) intraoperatively and the use of
alpha blockers after implantation was introduced (precise numbers not
reported).
Urinary symptoms were common following implantation in men who did not
have the symptom before treatment.
2.8% received adjuvant EBRT.
Page 133 of 261
Month 3
% (95% CI)
Median time to
resolution (months)
Frequency
33.5 (28.3–39.3)
12 (10–14)
Hesitancy
22.4 (18.1–27.4)
12 (9–14)
Urgency
42.0 (35.7–48.6)
14 (11–17)
Decreased force
40.3 (34.7–46.2)
10 (8–12)
Haematuria
3.7 (2.1–6.2)
not recorded
PSA
Mean 7.7 (SD±4.7) ng/mL
Study
Study design and quality
appraisal
Population
Urinary function
Page 134 of 261
Nocturia
32.4 (27.3–37.9)
10 (8–12)
Dysuria
31.6 (27–36.5)
9 (8–10)
Medication
27.5 (23.8–31.6)
30 (25–34)
Values are mean estimates (95% CI) from logistic regression models using
generalised estimating equation methods to account for within-subject
correlation—estimates are of men who did not report the particular symptom
at baseline.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Elshaikh et al 2003)
Case series
N: 402
Single centre, US
Level IV interventional
evidence
Age, years
Median 69
NHMRC case series quality
score: 3/6
Clinical stage
≤ T2
Overall quality assessment:
Moderate
Gleason score (range)
Median 6 (4–8)
Accrual: 1996–2001
Intermittent self-catheterisation for urinary retention was reported in 44 men
(10.9%) for a median duration of 6 weeks. Three patients eventually
underwent transurethral resection of the prostate for prolonged urinary
retention (> 10 months).
PSA
Median 6.45 ng/mL
(Schafer et al 2008)
Case series
Single centre, Germany
Level IV interventional
evidence
Accrual: June 1998 –
December 2003
NHMRC case series quality
score: 2/6
Overall quality assessment:
Poor
N: 258 (296 treated consecutively, 38 patients died
before assessment)
16% of men used pads for urinary incontinence at a median of 51 months
post implantation.
Age, years
Median 71
9.3%, 3.6%, 2.6% and 0.5% used one, two, three and four or more pads per
day.
Clinical stage
94% ≤ T2
Gleason score:
≤7
71%
≥8
0.4%
Unknown
28.6%
PSA
Median 7.3 ng/mL
Table notes:
3D-CRT = three-dimensional conformal radiotherapy; ADT = androgen deprivation therapy; EBRT = external beam radiotherapy; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer
quality of life questionnaire – prostate cancer module; EPIC = Expanded Prostate cancer Index Composite; HRQoL = health-related quality of life; IMRT = intensity modulated radiotherapy; IPSS = International Prostate
Symptom Score; LDRBT = low-dose-rate brachytherapy ; LUTS = lower urinary tract symptoms; NR = not reported; NS = not significant; RP = radical prostatectomy; RTOG = Radiation Therapy Oncology Group; UCLAPCI = University of California, Los Angeles – Prostate Cancer Index
Appendix E
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 32
Data tables for bowel side effects
Bowel side effects resulting from low-dose-rate brachytherapy, radical prostatectomy, external beam radiotherapy and active surveillance for the treatment of
localised prostate cancer
Study
Study design and quality
appraisal
Population
Bowel function
(Giberti et al 2009)
Randomised controlled trial
N: 100 RP patients and 100 LDRBT patients
Single centre, Italy
Level II interventional
evidence
Questionnaires were completed for 89 RP patients
and 85 LDRBT patients.
Mean scores from questionnaires at four time points (higher scores
indicate worse function/symptoms
Downs and Black quality
score: 19/27
Exclusion criteria were in accordance with
American Brachytherapy Society.
Accrual: May 1999 – October
2002
Overall quality assessment:
Moderate
RP
LDRBT
No. patients
100
100
Age, years
65.2
(57–74)
65.6
(56–74)
Gleason score
5.9
5.7
PSA, ng/mL
7.8
10.0)
7.5 (3.5–
(2.9–9.3)
Values are mean (range) unless otherwise
indicated.
Pre-treatment
6 months
1 year
5 years
2
2
3 (NS)*
6 (0.03)
2 (NS)
4 (NS)
2 (NS)
5 (NS)
3
1
4 (NS)
2 (NS)
4 (NS)
1 (NS)
3 (NS)
0 (NS)
4
5
4 (NS)
6 (NS)
6 (NS)
8 (NS)
5 (NS)
6 (NS)
EORTC-QLQ-PR25:
Bowel symptoms
RP
LDRBT
EORTC-QLQ:
Constipation
RP
LDRBT
Diarrhoea
RP
LDRBT
* p-values for change from pre-treatment value
(Eade et al 2008)
Prospective cohort
Single centre, US
Level III-2 interventional
evidence
N: 374 low-risk prostate cancer patients (as
defined by American Joint Committee on Cancer)
with Gleason score < 7
Downs and Black quality
score: 19/27
Overall quality assessment:
Moderate
LDRBT patients:
May 1998 – August 2004
EBRT patients:
Page 135 of 261
August 2001 – June 2004
EBRT
LDRBT
n
216
158
Age,
years
67.6 (27–81)
64.7 (42–78)
PSA, ng/mL
5.2 (0.4–9.6)
5.2 (0.5–9.8)
Values are median (range).
No patients were lost to follow-up.
Bowel outcomes, RTOG scale
EBRT
LDRBT
p-value
3.0 (1.9)
0
1.00
7.8
0.1
0.028
0.228
Acute side effects
GI Grade 2
GI Grade 3
5.0 (2.3)
0
Late side effects*
GI Grade 2
GI Grade 3
2.4
0
GI = gastrointestinal
Study
Study design and quality
appraisal
Population
Bowel function
Values are number (%) or %, unless otherwise noted.
Page 136 of 261
* 3-year actuarial risk
(Wong et al 2009)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: May 1993 – July
2004
Downs and Black quality
score: 19/27
N:853 consecutive patients with localised prostate
cancer*
n
LDRBT
GRADE
225
0
1
2+*
p (chi-square)
Grade 3
3D-CRT (%)
26
20
54
<0.0001
0
IMRT (%)
28
26
46
LDRBT (%)
77
14
8
Clinical stage:
Overall quality assessment:
Moderate
T1
T2
Maximum achieved RTOG acute gastrointestinal side effects
(< 3 months following treatment)
197 (88)
28 (12)
1
0
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
PSA ≤10 ng/mL
193 (86)
Gleason score ≤ 6
173 (77)
Adjuvant hormone
treatment
153 (68)
GRADE
Low-risk
158 (70)
0
1
2+*
p (chi-square)
Grade 3
0.0128
2
Maximum achieved RTOG late gastrointestinal side effects (> 3 months
following treatment)
3D-CRT (%)
57
26
17
3D-EBRT
IMRT
IMRT (%)
63
23
15
1
270
314
LDRBT (%)
72
15
13
1
120 (44)
123 (46)
231 (74)
69 (22)
* Grade 3 side effects are combined with grade 2 to prevent small numbers
in cells for chi-square test.
PSA ≤ ng/mL
192 (71)
238 (76)
Adjuvant
hormone
treatment
Four 3D-CRT patients, 2 LDRBT patients and no IMRT patients developed
grade 3 proctitis.
47 (17)
114 (36)
Low-risk
119 (44)
109 (35)
n
Clinical stage:
T1
T2
Loss to follow-up: none evident.
Values are n (%).
* See study profile for further details.
(Litwin et al 2004)
Prospective cohort
Multicentre, US
Level III-2 interventional
N: 1,584 consecutively recruited prostate cancer
patients
UCLA PCI scores for bowel function and bother (scale 0–100, with higher
scores representing better outcome)*
Study
Accrual: Not reported
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study design and quality
appraisal
evidence
Population
Downs and Black quality
score: 18/27
Age, years
Overall quality assessment:
Moderate
Bowel function
RP (n=1276)
61.2±6.8
Gleason score, %:
2–6
7
8–10
77
19
4
EBRT (n=99)
Age, years
70.9±6.1
Gleason score, %:
2–6
7
8–10
67
25
8
68.6±7.4
Gleason score, %:
2–6
7
8–10
EBRT
LDRBT
75±1.2
84±1.2
84±1.2
85±1.2
85±1.3
85±1.3
85±1.3
85±1.3
84±1.4
60±2.1
73±2.2
75±2.2
76±2.2
76±2.3
78±2.3
74±2.4
74±2.5
78±2.8
68±2.1
77±2.0
79±2.1
81±2.0
78±2.3
83±2.2
81±2.6
85±2.7
80±3.3
74±1.7
83±1.8
84±1.8
84±1.8
84±1.8
85±1.8
85±1.8
85±1.9
83±2.0
50±3.0
67±3.2
70±3.1
69±3.2
72±3.2
71±3.2
67±3.4
66±3.6
73±3.9
61±3.0
76±2.8
75±3.0
78±2.8
78±3.2
81±3.1
79±3.8
83±3.8
80±3.9
Bowel function:
0 months‡
3 months
6 months
9 months
12 months
15 months
18 months
21 months
24 months
Bowel bother:
LDRBT (n=209)
Age, years
RP
89
9
1
Values are mean±SD unless otherwise specified.
0 months†
3 months
6 months
9 months
12 months
15 months
18 months
21 months
24 months
* Based on 808 questionnaire responses
† Between-group comparison
‡ Score as measured immediately after treatment
Values are mean±SE.
(Hashine et al 2008)
Prospective cohort
Single centre, Japan
Level III-2 interventional
evidence
Accrual: January 2003 – July
2005
Page 137 of 261
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 213 (131 RP and 82 LDRBT patients)
RP
LDRBT p-value
Age, years*
(range)
68.0
70.5
0.016
(42–78) (50–85)
PSA, ng/mL*
9.6
6.7
Gleason score, n:
5–6
44
<0.001
<0.001
51
UCLA-PCI scores (mean±SD)*
RP
LDRBT
p-value†
89.8±19.5
78.7±16.3
83.2±16.5
87.5±15.9
86.0±16.7
84.9±18.1
82.8±20.8
84.1±18.6
83.8±17.4
87.5±18.9
0.055
0.032
0.478
0.276
0.201
Bowel function:
Baseline
1 month
3 months
6 months
12 months
Bowel bother:
Study
Study design and quality
appraisal
Population
Page 138 of 261
7
8–10
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Buron et al 2007)
Prospective cohort
Multicentre, France
Level III-2 interventional
evidence
Accrual: March 2001 – June
2002
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
Bowel function
42
36
27
4
Neoadjuvant
hormones
8
18
Nerve-sparing
22
-
EBRT
-
1
0.002
Baseline
1 month
3 months
6 months
12 months
90.8±17.9
84.0±22.6
88.8±20.8
93.6±15.3
93.6±16.2
91.1±17.2
85.4±22.9
85.5±17.8
81.8±22.8
90.4±18.8
0.913
0.580
0.081
0.002
0.188
* All UCLA-PCI scores were transformed to a scale of 0–100, with higher
scores representing better HRQoL.
* Median
† Mann-Whitney U test
N: 435 men with low-risk prostate cancer from 11
French hospitals treated with LDRBT (308) or RP
(127)
Bowel outcomes, EORTC QLQ-PR25
RP
LDRBT
Age, years
62.7±6
65.2±6.3
Neoadjuvant
hormones, %
6.3
43.5
IPSS
7.8
5.9
RP
LDRBT
2
8.9
0
15.1
Faecal incontinence worse
than baseline, %
24 months
More rectal bleeding than
baseline, %
24 months
Values are mean±standard deviation.
Loss to follow-up after 24 months was between
35% and 59% (n data not provided) depending on
treatment arm—see study profile for further details.
Note: p-values not provided; main in-text data summarised as no other exact
values could be determined from the graphical presentation of results.
Values are mean±standard deviation, unless
otherwise specified.
(Ferrer et al 2008)
Prospective cohort
Multicentre, Spain
Level III-2 interventional
evidence
Accrual: April 2003 – March
2005
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 841 organ-confined prostate cancer patients
RP
Age,
years
EBRT
LDRBT
Mean prostate specific HRQoL scores at 2-year follow-up for low-risk
patients by treatment group
RP
EBRT
LDRBT
98.9±2.3
94.1±11.2
97.7±6
64±5.5
69.2±5.5
66.9±6.5
EPIC* bowel
PSA,
ng/mL 7.9±3.3
10.1±7.9
6.9±2.3
Gleason
score 6.8±6.2
p-values for one-way comparison of HRQoL scores
6±1.1
5.7±4.4
Values are mean±standard deviation.
Loss to follow-up:
614 patients treated with LDRBT (275), RP (134)
EPIC bowel
RP vs EBRT
RP vs LDRBT
LDRBT vs EBRT
<0.001
NS
<0.001
* All EPIC items were answered on a 5-point Likert scale and transformed
Study
Study design and quality
appraisal
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Pickles et al 2010)
Retrospective cohort
Multicentre, Canada
Level III-2 interventional
evidence
Accrual: July 1998 – January
2001.
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
Population
Bowel function
and EBRT (205) were included in HRQoL analysis.
linearly to a scale of 0–100, with higher scores indicating better HRQoL.
N: 278 (139 LDRBT, 139 matched EBRT)
Side effects
LDRBT EBRT
Age, years
64
71
PSA, ng/mL
5.6
6.4
Gleason score, %:
≤6
7
ADT use, %
87.8
12.2
31.7
87.8
12.2
30.2
Radiation
dose, Gy
144
68
Acute grade 2
GI side effects
LDRBT
EBRT
p-value
4
5
NS†
14–15
8–9
4
3–4
NR
0.0183
Prevalence of late
grade 3–4 GI side effects:*
Values are median unless otherwise specified.
2 years
3 years
4 years
5 years
Overall
6–7
5–6
3–4
3–4
NR‡
Values are % or p-value as indicated.
* Data are estimates from graphical presentation of results in study.
† Not significant
‡ Although percentages were not reported, it was stated that GI side effects
was greater for EBRT than for LDRBT; the p-value is reported accordingly.
(Smith et al 2010)
Prospective cohort
Population-based, NSW,
Australia
Level III-2 interventional
evidence
Accrual: October 2000 – May
2003
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 4,542 men (3,195 with histologically confirmed
T1a–2c prostate cancer and 1,347 controls with no
diagnosis of prostate cancer, as indicated and
cross-checked with registry data)
Unadjusted mean bowel function (score range 0–100; higher scores
indicate better function)
All potential participants had to be physically and
mentally capable of a 30-minute telephone
interview in English.
Page 139 of 261
Cases, n
Controls, n
Potentially
eligible
3,195
1,347
Final analysis
1,636
495
AS
200
NA
RP
981
NA
EBRT
123
NA
Combined
Baseline
3 years
AS
83.9±17.9
86.7±16.4
Nerve-sparing
RP
89±12.0
88.1±13.9
Non-nervesparing RP
87.1±15.7
88.5±12.3
EBRT
86.4±16.5
84.5±15.8
Combined
EBRT/ADT
87±14.5
81.8±19.0
LDRBT
91.8±9.3
88.8±11.5
Controls
88.4±12.3
89.8
Study
Study design and quality
appraisal
Population
Bowel function
Page 140 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
EBRT/ADT
166
NA
LDRBT
58
NA
Unadjusted mean bowel bother (score range 0–100; higher scores
indicate better function)
Mean age, years
[95% CI]
61.2
[60.7, 61.7]
61.2
[61, 61.5]
Baseline
3 years
AS
84.3±28.3
88.1±23.2
Nerve-sparing
RP
93±18.4
90±20.9
Non-nervesparing RP
90.4±22.1
90.5±18.7
EBRT
87.6±25.9
79.8±28.2
Combined
EBRT/ADT
88.1±24.7
78.8±29.0
LDRBT
94.4±14.8
91.1±14.6
Controls
89.2±23.3
93.8
Moderate or severe bowel problems, n (%)
Baseline
3 years
AS
27 (13.5)
11 (6.3)
RP
43 (4.4)
32 (3.5)
EBRT
13 (10.6)
16 (14.5)
Combined
EBRT/ADT
15 (9.0)
19 (12.5)
LDRBT
0 (0.0)
0 (0.0)
Controls
5 (1.0)
NA†
† Controls were not asked the relevant questions at year 3.
(Frank et al 2007)
Retrospective cohort
Radiation oncology
department, US
Level III-2 interventional
evidence
Accrual: 1998–2000
Downs and Black quality
score: 16/27
Overall quality assessment:
N: 960 men treated with LDRBT (160), RP (400)
and HDR EBRT (400)
Age, years
LDRBT RP
EBRT
64
68
Values are median.
61
EPIC domain-specific prostate cancer HRQoL scores† (mean±SD)
LDRBT
EBRT
RP
Bowel
function
89.4±11.5
[86.8,92.1]
85.8±14.2
[83.4,88.2]
93±9
[91.8,94.2]
Bowel
86.4±16.8
85.1±19.8
94.6±10.4
Study
Study design and quality
appraisal
Moderate
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Population
Bowel function
Loss to follow-up:
625/960 (65%) in total completed a survey, of
whom 443 were found to have undergone
monotherapy and included in the analysis—see
study profile for further details.
bother
[82.5,90.3]
[81.7,88.5]
[93.2,95.9]
LDRBT was associated with significantly worse bowel function than RP
(p=0.018); worse bowel function was observed for EBRT than LDRBT
(p=0.03).
LDRBT was associated with significantly more bowel bother than RP
(p<0.001); bowel bother for EBRT and LDRBT was not statistically different.
† Higher scores indicate better HRQoL outcomes (scale 0–100).
(Guedea et al 2009)
Prospective cohort
Single centre, Spain
Level III-2 interventional
evidence
April 2003 – March 2005
N: 304 men with prostate cancer
Baseline EPIC scores†
LDRBT RP
EBRT
Intestinal summary
RP
EBRT
LDRBT
98.3±3.3
96.9±7.1
97.1±6
Downs and Black quality
score: 16/27
n
56
114
143
(no statistical difference between baseline scores)
Overall quality assessment:
Moderate
Age, years
67.5
63.9
68.8
Change in EPIC score at 2 years post treatment
PSA, ng/mL
6.4
7.9
11.9
Gleason score
5.7
6.3
6.4
Intestinal summary
RP
EBRT
LDRBT
0.03±6.1
–2.3±9.3
–0.4±9.3
(no statistical difference in changes in score at 2 years)
Values are mean and n as indicated
Change in EPIC score at 2 years post treatment, multivariate
generalised estimating equation (GEE) model*
Intestinal summary
RP
EBRT
LDRBT
0.81±1.62
–1.68±1.61
(reference)
(no statistical difference in changes in score at 2 years after adjusting for
age, risk group, use of hormones and pre-treatment scores)
† EPIC scores range 0–100, with higher scores indicating better HRQoL.
* Adjusting for age, baseline scores, risk group and hormonal treatment, at
2 years post treatment
Values are mean±SD unless otherwise indicated.
Page 141 of 261
(Wei et al 2002)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: June 1995 – May
1999
Downs and Black quality
N: 1,014 including 142 healthy male controls who
are not further considered‡
LDRBT
n
112
EPIC* bowel summary scores for follow-up exceeding 1 year
Bowel
LDRBT
76†# [72.2,79.8]
EBRT
RP
85.2†‡ [82.5,87.8]
93.2#‡ [92,94.5]
Study
Page 142 of 261
Study design and quality
appraisal
score: 16/27
Population
Overall quality assessment:
Moderate
Time since
primary therapy,
months
Bowel function
Age, years
67.2±7.3
* Expanded Prostate Cancer Index, values are mean [99% CI].
21
Multivariable modelling was used to adjust for age, time since therapy,
Gleason score, clinical stage, PSA and use of hormonal therapy.
Adjuvant/
neoadjuvant
therapy, %
51
† # ‡ Values that share a common symbol were significantly different in a
pairwise comparison (significance set at 0.008 after Tukey adjustment for
comparisons between three groups), p<0.0005.
PSA, ng/mL
9.7±14.9
Gleason score, %:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
2–6
7
8–10
68.3
23.2
8.5
EBRT
RP
n
203
896
Age, years
70.9±7.2
63.5±7.8
Time since
primary therapy,
months
29
30
Adjuvant/
neoadjuvant
therapy, %
33
28
PSA, ng/mL
9.1±12.7
7.3±7.2
Gleason score, %:
2–6
7
8–10
43.1
47.9
9.0
59.6
37.3
3.1
Values are median±SD, except where indicated.
‡ A control group of healthy males was
unnecessary for data extraction and irrelevant to
the research questions of this review.
(Tsui et al 2005)
Retrospective cohort
N: 202
Bowel symptoms based on RTOG late radiation morbidity scoring
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Single institution, Canada
Level III-2 interventional
evidence
Accrual: 1998–2000
Downs and Black quality
score: 15/27
Overall quality assessment:
Poor
Population
Bowel function
LDRBT
RT
Age, years
Mean±SD
64.8±6.5
66.3±5.1
PSA, ng/mL
Mean±SD
6.2 (2.3)
9.1 (3.7)
Gleason score, n (%):†
≤6
83 (97.6)
7
2 (2.4)
8
0 (0)
30 (40.5)
41 (55.4)
3 (4.1)
α-blocker, %
3.5
6.6
Neoadjuvant
ADT, %
32.9
13.2*
Values are mean±SD unless otherwise specified.
† p<0.001, *p=0.005
(Wyler et al 2009)
Retrospective cohort
Single centre, Switzerland
Accrual:
Level III-2 interventional
evidence
N: 212 consecutive patients with clinically localised
prostate cancer
BT patients, March 2001 –
December 2004
Downs and Black quality
score: 14/27
LDRBT
RP
n
70
142
EBRT patients, January 2002
– December 2004
Overall quality assessment:
Poor
Age, years
(range)
61 (49–75)
64 (47–75)
PSA, ng/mL
6.1
(1.1–12.8)
11.3
(0.3–24)
Gleason score
5.7 (4–7)
6.3 (5–9)
79% of LDRBT patients and 74% of RP patients
returned questionnaires.
system*
LDRBT†
EBRT‡
p-value
10.9
3.3
5.3
7.1
7.7
19
0
12.5
12.1
14.9
14.9
15.0
4.5
10.8
1.0
0.098
0.21
0.36
0.36
0.08
0.29
Bowel symptoms, %
6 months
12 months
18 months
24 months
30 months
36 months
42 months
* Large loss to follow-up with only data on 19 and 37 patients available for
analysis at the study end-point and two patients unaccounted for.
† n=86 at first follow-up (6 months)
‡ n=76 at first follow-up
Symptom scale outcomes (0–100, with higher scores indicating better
HRQoL)
5–12 months
13–24 months
37–53 months
40±43.5
33.3±47.1
12.5±17.3
3.3±10.5
11.1±19.2
0
Constipation
RP
LDRBT
No changes in bowel symptoms were observed within groups over time and
no statistically significant difference was observed between groups.
Diarrhoea
RP
LDRBT†
20±18.3
0
4.2±11.8*
13.3±17.2*
0
6.7±14.9
* Between-group comparison (Mann-Whitney U test), p=0.009
Page 143 of 261
† Within-group comparison (Kruskal-Wallis test), p=0.031
Number of patients for whom data were provided in results section is small
and does not agree with reporting elsewhere in the paper that 79% and 74%
of LDRBT and RP patients, respectively, returned questionnaires.
Page 144 of 261
Study
Study design and quality
appraisal
Population
Bowel function
(Pinkawa et al 2009)
Comparison of two matched
single arms
N: 104 (52 in each group).
Mean (quartiles) function and bother scores from the EPIC
questionnaire†
Level III-3 interventional
evidence
Single centre, Germany
Accrual: 2003–2006
LDRBT
EBRT
Age, years
(range)
68 (51–77)
68 (48–77)
Downs and Black quality
score: 16/27
PSA, ng/mL
7
14)
8 (1.5–
(2.5–24)
Overall quality assessment:
Moderate
Gleason
score < 7
50 (96)
39 (75)
EBRT
LDRBT
Values are median (range) or n (%).
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Time A§
Time B
Time C
93
(88;96;100)
94
(92;96;100)
77
(65;81;92)
81
(71;85;96)
89
(82;92;96)
93
(92;96;100)
95
(93;100;100)
94
(93;100;100)
76
(58;83;96)
82
(75;89;100)
87
(79;96;100)
93
(93;100;100)
Bowel function:
Bowel bother:
EBRT
LDRBT
† EPIC scale 0–100, with higher scores representing better HRQoL.
No significant differences were observed between treatment groups
(p=0.05).
Quartiles = 25th, 50th and 75th percentiles.
Comparison of function and bother scores from the EPIC questionnaire
Time A vs B, p-value
Time A vs C, p-value
<0.01
<0.01
<0.05
NS
<0.01
<0.01
<0.01
NS‡
Bowel function:
EBRT
LDRBT
Bowel bother:
EBRT
LDRBT
§ Time A = before LDRBT/EBRT, Time B = 1 month after LDRBT / on the
last day of EBRT, Time C = median 16 months after LDRBT/EBRT.
‡ Not significant (p=0.05)
Selected symptoms from the EPIC questionnaire
Time A (%)
Bloody stools
≥ rarely:
Time B (%)
Time C (%)
Study
Study design and quality
appraisal
Population
Bowel function
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
EBRT
LDRBT
8
12
14
12
17
12
19
12
52*
27
35†
15
2
2
33
18
12†
2
Painful bowel
movements ≥ rarely:
EBRT
LDRBT
Moderate/big problem
from increased frequency
of bowel movements:
EBRT
LDRBT
* p<0.01, † p<0.05 (responses in EBRT group are significantly different than
in the LDRBT group)
(Keyes et al 2009)
Case series
N=712 eligible from 932 consecutive patients
Multicentre, Canada
Level IV interventional
evidence
Age, years
Median 65.5 (46–82)
NHMRC case series quality
score: 5/6
Clinical stage
< T2c
Overall quality assessment:
Good
Gleason score
≤7
Accrual: July 1998 – June
2003
PSA, ng/mL:
≤ 10
10 – ≤ 15
RTOG side effects of Grade 2 or greater in 9.8%.
85.8%
14.2%
Follow-up at least 34 months:
144 excluded due to living in remote area, 35 less
than 34 months follow-up, 41 with insufficient data.
Page 145 of 261
(Zelefsky et al 2007a)
Case series
N:562
Single centre, US
Level IV interventional
evidence
Age
Not reported
NHMRC case series quality
score: 5/6
Clinical stage
99.8% ≤ T2
Overall quality assessment:
Gleason score
Accrual: January 1998 –
December 2004
NCI CTCAE bowel side effects:
Late grade 2 6%
Late grade 3 1%
Study
Study design and quality
appraisal
Good
Population
Bowel function
99.8% ≤ 7
Page 146 of 261
PSA, ng/mL:
≤ 10
10 – ≤ 20
> 20
94.5%
5.3%
0.2%
(Kao et al 2008)
Case series
N: 643 men with localised prostate cancer
Single centre, US
Level IV interventional
evidence
Age
Not reported
NHMRC case series quality
score: 4/6
Clinical stage
T1a – T2c
Overall quality assessment:
Moderate
Gleason score
98.8% of patients ≤ 7
Accrual: June 1995 –
February 2005
Freedom from grade 2 or higher rectal bleeding at 3 and 5 years was
reported for 91.2% and 88.5% of patients respectively.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
PSA
Median = 6.1 ng/mL
Loss to follow-up:
Patient numbers available for bowel outcomes
unclear.
(Eckman et al 2010)
Case series
N: 394
Single centre, US
Level IV interventional
evidence
Age, years
Mean 67.3 (SD±7.6)
NHMRC case series quality
score: 3/6
Clinical stage
99.5% < T3
Overall quality assessment:
Moderate
Gleason score
95.7% < 8
Accrual: 1995 – 2007
PSA
Mean 7.7 (SD±4.7) ng/mL
Bowel symptoms were uncommon following treatment, although rectal
bleeding increased to a peak of 26.8% [20.4–34.3] at 18 months among men
who did not report rectal bleeding at baseline. At 5 years, 17.6% [13.2–23.1]
of men continued to report rectal bleeding. The median time to the resolution
of rectal bleeding was 19 months [12.9–24.0].
Values are mean estimates (95% CI) from logistic regression models using
generalised estimating equation methods to account for within subject
correlation.
2.8% received adjuvant EBRT.
(Schafer et al 2008)
Case series
Single centre, Germany
Level IV interventional
evidence
Accrual: June 1998 –
December 2003
NHMRC case series quality
score: 2/6
Overall quality assessment:
Poor
N: 258 (296 treated consecutively, 38 patients died
before assessment)
2.8% of men suffered ‗moderate‘ to ‗strong‘ faecal incontinence at a median
of 51 months following implantation.
Age, years
Median 71
1.9% of men suffered ‗moderately‘ to ‗strongly‘ bloody stools at a median of
51 months following implantation.
Clinical stage
94% ≤ T2
Gleason score:
Study
Study design and quality
appraisal
Population
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
≤7
≥8
Unknown
Bowel function
71%
0.4%
28.6%
PSA
Median 7.3 ng/mL
Table notes:
3D-CRT = three-dimensional conformal radiotherapy; ADT = androgen deprivation therapy; LDRBT = low-dose-rate brachytherapy; CTCAE = common toxicity criteria for adverse events; EBRT= external beam
radiotherapy; EORTC QLQ-PR25 = European Organisation for Research and Treatment of Cancer quality of life questionnaire – prostate cancer module; EPIC = Expanded Prostate cancer Index Composite; HRQoL =
health-related quality of life; IMRT = intensity modulated radiotherapy; NA = not assessed; RP = radical prostatectomy; RTOG = Radiation Therapy Oncology Group; UCLA-PCI = University of California, Los Angeles –
Prostate Cancer Index
Page 147 of 261
Appendix F
Page 148 of 261
Table 33
Data tables for sexual dysfunction side effects
Sexual dysfunction resulting from low-dose-rate brachytherapy, radical prostatectomy, external beam radiotherapy and active surveillance for the treatment
of localised prostate cancer
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Population
Sexual function
(Giberti et al 2009)
Randomised controlled trial
N: 100 RP patients and 100 LDRBT patients
Single centre, Italy
Level II interventional
evidence
Questionnaires were completed for 89 RP patients
and 85 LDRBT patients
Mean scores from questionnaires at four time points (higher scores
indicate worse function/symptoms)
Downs and Black quality
score: 19/27
Exclusion criteria were in accordance with
American Brachytherapy Society.
Accrual: May 1999 – October
2002
Overall quality assessment:
Moderate
RP
LDRBT
No. patients
100
100
Age, years
65.2
(57–74)
65.6
(56–74)
Gleason score
5.9
5.7
PSA, ng/mL
7.8
10)
7.5 (3.5–
(2.9–9.3)
Values are mean (range) unless otherwise
indicated.
Pre-treatment
6 months
1 year
5 years
9 (0.03)
10 (0.03)
7 (NS)
7 (NS)
7 (NS)
8 (NS)
6
6
10 (0.03)
11 (0.02)
8 (NS)
8 (NS)
8 (NS)
8 (NS)
23.2
22.9
16.3 (0.02)
18.5 (0.03)
22.2 (NS)
21.9 (NS)
22 (NS)
21.2 (NS)
EORTC-QLQ-PR25:
Sexual function
RP
LDRBT
5
6
Sexual activity
RP
LDRBT
IIEF:
RP
LDRBT
Percentage of patients reporting good erectile function (mean IIEF
score > 22, scale 0–25)
Pre-treatment
6 months
1 year
5 years
(Buron et al 2007)
Prospective cohort
Multicentre, France
Level III-2 interventional
evidence
Accrual:
Downs and Black quality
N: 435 men with low-risk prostate cancer from 11
French hospitals treated with LDRBT (308) or RP
(127)
RP
LDRBT
RP
LDRBT
62
40
68
65
60
58
78
68
Sexual outcomes, EORTC QLQ-PR25
RP
Erectile function worse
LDRBT
Study
March 2001 – June 2002
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study design and quality
appraisal
score: 17/27
Population
Overall quality assessment:
Moderate
Neoadjuvant
hormones (%)
6.3
43.5
IPSS
7.8
5.9
Age, years
Sexual function
62.7±6
65.2±6.3
Values are mean±standard deviation.
Loss to follow-up after 24 months was between
35% and 59% (N data not provided) depending on
treatment arm—see study profile for further details.
(Ferrer et al 2008)
Prospective cohort
Multicentre, Spain
Level III-2 interventional
evidence
Accrual: April 2003 – March
2005
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
Prospective cohort
Single centre, Japan
Level III-2 interventional
evidence
Accrual: January 2003 – July
2005
Page 149 of 261
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
6 months
18 months
88
83.3
50.8
45.8
32
12.5
Treatment of impotence, %:
12 months
Note: p-values not provided; main in-text data summarised as no other exact
values could be determined from the graphical presentation of results.
Values are mean±standard deviation, unless
otherwise specified.
* Among sexually active men
N: 841 organ-confined prostate cancer patients
Neo-adjuvant hormonal therapy among RP patients was 6.3% compared
with 43.5% among LDRBT patients.
RP
EBRT
LDRBT
Mean HRQoL scores at 2-year follow-up for low-risk patients by
treatment group
Age,
years
64±5.5
69.2±5.5
66.9±6.5
EPIC* sexual
PSA,
ng/mL
7.9±3.3
10.1±7.9
6.9±2.3
p-values for one-way comparison of HRQoL scores
6±1.1
5.7±4.4
Gleason
score
6.8±6.2
Values are mean±standard deviation.
(Hashine et al 2008)
than baseline*, %:
EPIC sexual
RP
EBRT
LDRBT
33±21.6
42.2±22.5
50.5±23.9
RP vs EBRT
RP vs LDRBT
LDRBT vs EBRT
<0.001
<0.001
<0.001
Loss to follow-up:
614 patients treated with LDRBT (275), RP (134)
and EBRT (205) were included in HRQoL analysis.
* All EPIC items were answered on a 5-point Likert scale and transformed
linearly to a scale of 0 to 100, with higher scores indicating better HRQoL.
N: 213 (131 RP and 82 LDRBT patients)
UCLA-PCI scores (mean±SD)*
RP
LDRBT p-value
Age, years*
(range)
68.0
70.5
0.016
(42–78) (50–85)
PSA, ng/mL*
9.6
6.7
Gleason score, n:
5–6
44
<0.001
<0.001
51
RP
LDRBT
p-value†
43.4±25.1
2.7±8.1
2.5±6.7
3.6±8.2
5.2±11.0
32.4±29.1
29.6±25.4
29.7±24.6
35.3±26.7
26.4±24.4
0.416
<0.001
<0.001
<0.001
<0.001
Sexual function:
Baseline
1 month
3 months
6 months
12 months
Study
Study design and quality
appraisal
Population
Page 150 of 261
7
8–10
Sexual function
42
36
27
4
Neoadjuvant
hormones
8
18
Nerve-sparing
22
-
EBRT
-
1
Sexual bother:
0.002
Baseline
1 month
3 months
6 months
12 months
67.6±31.3
59.6±37.4
58.2±36.4
53.8±35.8
51.6±35.0
75.4±26.3
78.3±27.8
69.6±28.0
76.7±27.5
73.8±31.9
0.146
0.005
0.111
0.002
<0.001
* All UCLA-PCI scores were transformed to a scale of 0 –100, with higher
scores representing better HRQoL
*Median
† Mann-Whitney U test
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Smith et al 2010)
Prospective cohort
Population-based, NSW,
Australia
Level III-2 interventional
evidence
Accrual: October 2000 – May
2003
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 4542 men (3,195 with histologically confirmed
T1a–2c prostate cancer and 1,347 controls with no
diagnosis of prostate cancer, as indicated and
cross-checked against registry data)
Unadjusted mean sexual function (score range 0–100; higher scores
indicate better function), mean±SD
All potential participants had to be physically and
mentally capable of a 30-minute telephone
interview in English
Cases, n
Controls, n
Potentially
eligible
3,195
1,347
Final analysis
1,636
495
AS
200
NA
RP
981
NA
EBRT
123
NA
Combined
EBRT/ADT
166
NA
LDRBT
58
NA
Mean age, years
[95% CI]
61.2
61.2
[60.7, 61.7] [61, 61.5]
Note: Patients who received high-dose-rate BT and
ADT alone were also assessed in the study, but
were not considered for the purposes of this
review.
Baseline
3 years
AS
61.0±24.8
44.1±29
Nerve-sparing
RP
71.8±21.7
34.7±27.7
Non-nervesparing RP
63.3±26.8
22±23.6
EBRT
57.4±28.0
32.0±29.0
Combined
EBRT/ADT
50.6±28.6
22.1±25.9
LDRBT
69.8±25.2
54.0±25.7
Controls
66.0±25.7
57.1
Unadjusted mean sexual bother (score range 0–100; higher scores
indicate better function), mean±SD
Baseline
3 years
AS
67.0±37.2
65.9±37.9
Nerve-sparing
RP
78.9±32.0
52.2±39.7
Non-nervesparing RP
71.1±36.5
53.6±42.2
EBRT
74.6±33.5
57.6±41.9
Study
Study design and quality
appraisal
Population
Sexual function
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Combined
EBRT/ADT
65.1±37.9
58.4±42.2
LDRBT
81.9±29.5
66.8±32.7
Controls
75.3±34.0
78.5
Impotence, n (%)
Baseline
3 years AS
53 (27.3)
94 (54.3)
RP
206 (21.5)
695 (77.4)
EBRT
35 (30.2)
72 (67.9)
Combined
EBRT/ADT
63 (39.1)
121 (82.3)
LDRBT
11 (19.0)
20 (36.4)
Controls
109 (23.3)
NA†
† Controls were not asked the relevant questions at year 3.
(Frank et al 2007)
Retrospective cohort
N: 960 men treated with LDRBT (160), RP (400)
and HDR EBRT (400)
Radiation oncology
department, US
Level III-2 interventional
evidence
Accrual: 1998–2000
Downs and Black quality
score: 16/27
Age, years
Overall quality assessment:
Moderate
Loss to follow-up:
625/960 (65%) in total completed a survey, of
whom 443 were found to have undergone
monotherapy and were included in the analysis—
see study profile for further details.
LDRBT RP
EBRT
64
68
61
Values are median.
EPIC domain specific prostate cancer HRQoL scores† (mean±SD) [95%
CI]
LDRBT
EBRT
RP
Sexual
function
37.8±27.2
[31.5,44.1]
28±27.9
[23.3,32.8]
25.1±24.5
[21.9,28.2]
Sexual
bother
49.4±31.9
[42,56.8]
50.2±36.7
[43.9,56.4]
44.7±31.8
[40.6,48.8]
LDRBT patients had significantly better sexual function than patients treated
with EBRT (p<0.01) and RP (p<0.001).
No difference in sexual bother was observed among the three treatment
modalities (p=0.35).
† Higher scores indicate better HRQoL outcomes (scale 0–100).
Page 151 of 261
(Guedea et al 2009)
Prospective cohort
Single centre, Spain
Level III-2 interventional
evidence
April 2003 – March 2005
Downs and Black quality
score: 16/27
N: 304 men with prostate cancer
n
Baseline EPIC scores*
LDRBT RP
EBRT
56
143
114
Sexual summary
RP
EBRT
LDRBT
58.3±24
50.3±24.6
54.0±25.4
Study
Page 152 of 261
Study design and quality
appraisal
Population
Sexual function
Overall quality assessment:
Moderate
Age, years
67.5
63.9
68.8
PSA, ng/mL
6.4
7.9
11.9
Gleason score
5.7
6.3
6.4
Values are mean and n as indicated.
Comparison of EPIC scores at baseline
Sexual summary, p-value
RP vs LDRBT
NS‡ RP
vs EBRT
0.041§
EBRT vs LDRBT
NS
Overall
<0.001†
‡ Not significant
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
§ Tukey‘s studentised comparison
Change in EPIC score at 2 years post treatment
RP
EBRT
LDRBT
–26.6±27.4
–6.9±27.3
–6.3±27.3
EPIC
Sexual summary
Comparison of EPIC scores after 2 years
Sexual summary, p-value
RP vs LDRBT
<0.05
RP vs EBRT
<0.05
EBRT vs LDRBT
NR**
Overall
<0.001†
** Not reported
† ANOVA
Change of EPIC score at 2 years post treatment, multivariate
generalised estimating equation (GEE) model#
RP
EPIC
EBRT
LDRBT
Study
Study design and quality
appraisal
Population
Sexual function
Sexual summary
–18.74±4.46
–3.39±4.44
(reference)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Comparison of treatment scores after 2 years, GEE model
Sexual summary, p-value
LDRBT vs RP
<0.001#
RP vs EBRT
NR
EBRT vs LDRBT
NR
# Adjusting for age, baseline scores, risk group and hormonal treatment, at
2 years post treatment
* EPIC scores in range 0–100, with higher scores indicating better HRQoL
Values are mean±SD unless otherwise indicated.
(Wei et al 2002)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: June 1995 – May
1999
N: 1,014 including 142 male controls who are not
further considered‡
LDRBT
EPIC* sexual summary scores for follow-up exceeding 1 year
Sexual
LDRBT
EBRT
RP
38.8† [32.3,45.3]
33.9 [29.6,38.1]
Downs and Black quality
score: 16/27
n
114
Age, years
67.2±7.3
Overall quality assessment:
Moderate
Time since
primary therapy,
months
21
Adjuvant/
neoadjuvant
therapy, %
Multivariable modelling was used to adjust for age, time since therapy,
Gleason score, clinical stage, PSA and use of hormonal therapy.
51
PSA, ng/mL
9.7±14.9
† Values that share a common symbol were significantly different in a
pairwise comparison (significance set at 0.008 after Tukey adjustment for
comparisons between three groups), p<0.007.
26.9† [18.2,35.6]
* Expanded Prostate Cancer Index, values are mean [99% CI].
Gleason score, %:
Page 153 of 261
2–6
7
8–10
n
68.3
23.2
8.5
EBRT
RP
203
896
Study
Study design and quality
appraisal
Population
Age, years
Sexual function
70.9±7.2
63.5±7.8
Page 154 of 261
Time since
primary therapy,
months
29
30
Adjuvant/
neoadjuvant
therapy, %
33
28
PSA, ng/mL
9.1±12.7
7.3±7.2
Gleason score, %:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
2–6
7
8–10
43.1
47.9
9.0
59.6
37.3
3.1
Values are median±SD, except where indicated.
‡ A control group of healthy males was
unnecessary for data extraction and irrelevant to
the research questions of this review.
(Tsui et al 2005)
Retrospective cohort
Single institution, Canada
Level III-2 interventional
evidence
Accrual: 1998–2000
N: 202
N
Downs and Black quality
score: 15/27
Age, years
Overall quality assessment:
Poor
PSA (ng/mL)
Mean±SD
Mean±SD
Potency with and without sildenafil use*
LDRBT
RT
86
76
64.8±6.5
66.3±5.1
6.2 (2.3)
9.1 (3.7)
Gleason score, n (%):†
83 (97.6)
2 (2.4)
0 (0)
30 (40.5)
41 (55.4)
3 (4.1)
α-blocker, %
3.5
6.6
Neoadjuvant
ADT, %
32.9
13.2*
≤6
7
8
LDRBT†
EBRT‡
p-value
69.2
73.9
76.2
79.2
84.2
70
90
53.3
56.3
42.1
69.2
72.7
77.8
100
0.34
0.31
0.052
0.69
0.64
1.0
1.0
88.5
95.7
90.9
100
100
75
68.8
47.4
84.6
81.8
0.39
0.033
0.005
0.12
0.13
Patients potent without
sildenafil use, %:
6 months
12 months
18 months
24 months
30 months
36 months
42 months
Patients potent with
sildenafil use, %:
6 months
12 months
18 months
24 months
30 months
Study
Study design and quality
appraisal
Population
Sexual function
Values are mean±SD unless otherwise specified.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
† p<0.001, * p=0.005
36 months
42 months
90
100
100
100
1.0
1.0
* Prevalence of PDE5 inhibitor use was not reported, and authors admit that
LDRBT patients were often encouraged to use PDE5 inhibitors whereas
EBRT patients were seldom offered PDE5 inhibitors.
Large loss to follow-up with data on only 10 and 7 patients for the LDRBT
and EBRT groups, respectively, available for analysis at the study end-point
and two patients unaccounted for.
† n=35 at first follow-up (6 months)
‡ n=32 at first follow-up
(Pinkawa et al 2009)
Single centre, Germany
Accrual: 2003–2006
Comparison of two matched
single arms
N: 104 (52 in each group)
Level III-3 interventional
evidence
Age, years
Downs and Black quality
score: 16/27
Overall quality assessment:
Moderate
PSA, ng/mL
LDRBT
EBRT
68 (51–77)
68 (48–77)
7 (1.5–14)
8 (2.5–24)
Mean (quartiles) function and bother scores from the EPIC
questionnaire†
EBRT
Gleason score
< 7, n (%)
50 (96)
39 (75)
Neoadjuvant
hormones, n (%) 14 (27)
14 (27)
Values are median (range) unless otherwise
specified.
Time A§
Time B
Time C
43
(29;44;56)
46
(32;50;62)
32
(17;30;50)
36
(17;37;60)
37
(12;32;59)
42
(25;41;59)
67
(44;81;100)
72
(50;75;100)
54
(25;50;88)
58
(30;53;83)
60
(31;69;94)
61
(31;63;88)
Sexual function:
LDRBT
Sexual bother:
EBRT
LDRBT
§ Time A = before LDRBT/EBRT, Time B = 1 month after LDRBT / on the
last day of EBRT, Time C = median 16 months after LDRBT/EBRT
No statistically significant differences were observed between treatment
groups, p=0.05.
Quartiles = 25th, 50th and 75th percentiles.
Page 155 of 261
Comparison of function and bother scores from the EPIC questionnaire
Time A vs B, p-value
Time A vs C, p-value
<0.01
<0.01
Sexual function:
EBRT
Study
Study design and quality
appraisal
Population
Sexual function
LDRBT
<0.01
<0.01
<0.01
<0.01
<0.01
<0.05
Page 156 of 261
Sexual bother:
EBRT
LDRBT
Other sexual outcomes
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
LDRBT
EBRT
Patients with erectile
ability before treatment, n
44
42
Patients with erectile ability
post-treatment #, %
81
84
Patients with erections sufficient
for sex before treatment, n
29
31
Patients with erections sufficient
for sex post-treatment ‡, %
67
51
† EPIC scale 0–100, with higher scores representing better HRQoL
# among patients with erectile ability before treatment
‡ among patients with erections sufficient for sex before treatment
(Keyes et al 2009)
Case series
N: 712 eligible from 932 consecutive patients
Multicentre, Canada
Level IV interventional
evidence
Age, years
Median 65.5 (46–82)
NHMRC case series quality
score: 5/6
Clinical stage
< T2c
Overall quality assessment:
Good
Gleason score
≤7
Accrual: July 1998 – June
2003
PSA
≤ 10 ng/mL
85.8%
10 – ≤ 15 ng/mL 14.2%
Follow-up at least 34 months:
144 excluded due to living in remote area, 35 less
than 34 months follow-up, 41 with insufficient data.
Erectile function at least 12 months following LDRBT in men with known
baseline erectile function (n=706) had remained unchanged or improved for
59.5% and had worsened in 40.5%.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Population
Sexual function
(Kao et al 2008)
Case series
N: 643
Single centre, US
Level IV interventional
evidence
Age
Not reported
Potency was preserved in 86.8% and 73.4% patients after 3 and 5 years
respectively.
NHMRC case series quality
score: 4/6
Clinical stage
T1a–T2c
Overall quality assessment:
Moderate
Gleason score
98.8% of patients ≤ 7
Accrual: June 1995 –
February 2005
PSA
Median = 6.1 ng/mL
Loss to follow-up:
Erectile function data were available for 572 men,
of whom 420 were potent and assessed following
treatment.
(MacDonald et al 2005)
Case series
N: 342 men potent at baseline
Single centre, Canada
Level IV interventional
evidence
Age, years
Median 65 (49–80)
NHMRC case series quality
score: 4/6
Clinical stage
≤ T2
Overall quality assessment:
Moderate
Gleason score
≤7
Accrual: July 1998 – January
2002
PSA, ng/mL
Mean 6.7 (SD±3.3)
ED at 1 year (%)
ED at 2 years (%)
ED at 3 years (%)
Physiciandocumented
Patientdocumented
57
48
38
70
66
NR
Response rates for patient documented sexual function dropped to 52% at
year 2. Physician-documented sexual function was for 98%, 99% and 58%
of patients at year 1, 2 and 3 respectively.
Prostate volume < 50 cc
Page 157 of 261
(Eckman et al 2010)
Case series
N: 394
Single centre, US
Level IV interventional
evidence
Age, years
Mean 67.3 (SD±7.6)
NHMRC case series quality
score: 3/6
Clinical stage
99.5% < T3
Overall quality assessment:
Moderate
Gleason score
95.7% < 8
Accrual: 1995–2007
PSA, ng/mL
Mean 7.7 (SD±4.7)
2.8% received adjuvant EBRT.
Month 3, %
[95% CI]
Median time to
resolution, months
[95% CI]
Impaired potency
25.4 [17.6, 35.1]
45 [23–60]
Blood in semen
11.9 [4.9, 26.2}
not reported
Painful ejaculation
23.1 [10.5, 43.4]
not reported
Medication for ED
2.8 [1.8, 4.4]
not reported
Values are mean estimates (95% CI) from logistic regression models using
generalised estimating equation methods to account for within subject
correlation—estimates are of men who did not report the particular symptom
Study
Study design and quality
appraisal
Population
Sexual function
at baseline.
Page 158 of 261
Impaired potency continued to increase following treatment and was
reported in 42.6% [33.4, 52.4] of men at 5 years. The use of medication also
continued to increase and reached 21.5% [17.2, 26.4] by 5 years.
Table notes:
3D-CRT = three-dimensional conformal radiotherapy; ADT = androgen deprivation therapy; LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; EORTC QLQ-PR25 = European Organisation for
Research and Treatment of Cancer quality of life questionnaire – prostate cancer module; EPIC = Expanded Prostate cancer Index Composite; HRQoL = health-related quality of life; IIEF = International Index of
Erectile Function; IMRT = intensity modulated radiotherapy; NR = not reported; RP = radical prostatectomy; UCLA-PCI = University of California, Los Angeles – Prostate Cancer Index
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Appendix G
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 34
Data tables for health-related quality of life
Effects on health-related quality of life resulting from low-dose-rate brachytherapy, radical prostatectomy, external beam radiotherapy and active surveillance
for the treatment of localised prostate cancer
Study
Study design and quality
appraisal
Population
General health-related quality of life
(Giberti et al 2009)
Randomised controlled trial
N: 100 RP patients and 100 LDRBT patients
Single centre, Italy
Level II interventional
evidence
Questionnaires were completed for 89 RP patients
and 85 LDRBT patients.
Mean scores from questionnaires at four time points (higher scores
indicate worse function/symptoms)
Downs and Black quality
score: 19/27
Exclusion criteria were in accordance with
American Brachytherapy Society.
Accrual: May 1999 – October
2002
Overall quality assessment:
Moderate
RP
LDRBT
No. patients
100
100
Age, years
65.2
(57–74)
65.6
(56–74)
Gleason score
5.9
5.7
PSA, ng/mL
7.8
10)
7.5 (3.5–
(2.9–9.3)
Values are mean (range) unless otherwise
indicated.
Pre-treatment
1 year
5 years
86 (0.02)
90 (0.03)
86 (0.02)
90 (0.03)
90 (NS)
94 (NS)
87 (0.01)
90 (0.02)
90 (NS)
93 (NS)
90 (NS)
94 (NS)
87 (0.02)
86 (0.01)
86 (0.03)
84 (0.03)
84 (NS)
82 (NS)
88 (0.04)
88 (NS)
90 (NS)
88 (NS)
90 (NS)
88 (NS)
84 (0.02)
87 (0.02)
89 (NS)
93 (NS)
89 (NS)
94 (NS)
74 (0.02)
79 (0.03)
78 (NS)
81 (NS)
78 (NS)
82 (NS)
20 (0.03)
22 (0.02)
18 (NS)
19 (NS)
18 (NS)
18 (NS)
EORTC-QLQ
Physical function:
RP
91
LDRBT 94
Role function:
RP
93
LDRBT 95
Emotional function:
RP
82
LDRBT 80
Cognitive function:
RP
91
LDRBT 87
Social function:
RP
89
LDRBT 92
Global health:
RP
79
LDRBT 83
Page 159 of 261
6 months
Fatigue:
RP
16
LDRBT 17
Nausea/vomiting:
Study
Study design and quality
appraisal
Population
General health-related quality of life
Page 160 of 261
RP
0
LDRBT 0
1 (NS)
2 (NS)
1 (NS)
2 (NS)
1 (NS)
1 (NS)
12 (0.02)
15 (<0.01)
9 (NS)
8 (NS)
9 (NS)
8 (NS)
8 (NS)
11 (NS)
8 (NS)
10 (NS)
8 (NS)
11 (NS)
24 (0.04)
21 (NS)
23 (NS)
20 (NS)
22 (NS)
20 (NS)
4 (NS)
4 (NS)
4 (NS)
4 (NS)
3 (NS)
4 (NS)
Pain:
RP
8
LDRBT 5
Dyspnoea:
RP
8
LDRBT 9
Insomnia:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
RP
21
LDRBT 20
Appetite loss:
RP
3
LDRBT 5
(Lee et al 2001)
Prospective cohort
N: 90
Single institution, US
Level III-2 interventional
evidence
All patients treated between May 1998 and June
1999 (n=98) were offered enrolment. 90 patients
(91%) agreed to complete the FACT-P and IPSS
questionnaire.
Accrual: May 1998 – June
1999
Downs and Black quality
score: 22/27
Overall quality assessment:
Moderate
FACT-P scores at baseline, 1, 3 and 12 months following treatment
T0
T1
T3
T12
LDRBT 138.4 (±17.0)
120.5 (±21.7)
130.0 (±18.4)
138.5 (±14.2)
EBRT
137.1 (±12.1)
129.5 (±21.0)
134.4 (±19.2)
136.9 (±15.6)
LDRBT
RP
138.3 (±14.7)
117.7 (±18.3)
N
44
Age, years
67.1 (49–79)
By 12 months following treatment, there were no differences in mean FACTP score in any treatment group compared to baseline.
Stage, n (%)
T1
T2
26 (59)
18 (41)
PSA, ng/mL
6.5 (1.3–13.5)
Gleason score n (%):
≤6
7
>7
38 (86)†
6 (14)
0 (0)
EBRT
134.4 (±17.8)
140.4 (±14.9)
Men treated with LDRBT and RP experienced a greater decline in FACT-P in
the first month than men treated with EBRT (p=0.0288 and 0.0132
respectively). There was no statistical difference in FACT-P between the RP
and LDRBT groups.
Adjusting for baseline FACT-P score, age, race, clinical stage, pre-treatment
hormonal therapy and Gleason score, treatment remained a significant
predictor of FACT-P score at 1 month (p=0.0434).
Study
Study design and quality
appraisal
Population
General health-related quality of life
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
N
23
Age, years
68.8 (51–79)
Stage, n (%)
T1
T2
12 (52)
11 (48)
PSA, ng/mL
8.1 (2.9–19.6)
Gleason score n (%):
≤6
7
>7
11 (48)
10 (43)
2 (9)
N
23
Age, years
61.0 (42–68)*
RP
Stage, n (%)
T1
T2
19 (83)
4 (17)
PSA, ng/mL
6.2 (1.3–12.0)
Gleason score n (%):
16 (69)
5 (22)
2 (9)
≤6
7
>7
Values are median (range) or n (%).
† significantly more Gleason ≤ 6 than RP or EBRT
(p=0.015), * significantly younger than LDRBT or
EBRT (p=0.0006).
Page 161 of 261
(Buron et al 2007)
Prospective cohort
Multicentre, France
Level III-2 interventional
evidence
N: 435 men with low-risk prostate cancer from 11
French hospitals treated with LDRBT (308) or RP
(127)
Downs and Black quality
score: 17/27
Age, years
Overall quality assessment:
Neoadjuvant
Accrual:
March 2001 – June 2002
RP
LDRBT
62.7±6
65.2±6.3
Intragroup QLQ-C30 score changes over time#
MeanRP (p-value*)
MeanBT (p-value*)
–18.0 (<0.0001)
–28.7 (<0.0001)
–48.3 (<0.0001)
–5.8 (<0.0001)
–2.8 (<0.0001)
–7.2 (<0.0001)
T0–TE†
Global health
Physical functioning
Role functioning
Study
Study design and quality
appraisal
Moderate
Population
General health-related quality of life
Page 162 of 261
hormones (%)
6.3
43.5
IPSS
7.8
5.9
Values are mean±standard deviation
Loss to follow-up after 24 months was between
35% and 59% (N data not provided) depending on
treatment arm—see study profile for further details.
Values are mean±SD, unless otherwise specified.
Emotional functioning
Cognitive functioning
Social functioning
Fatigue
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
–6.4 (0.0139)
–7.6 (0.0019)
–40.5 (<0.0001)
38.1 (<0.0001)
28.9 (<0.0001)
8.5 (0.0022)
15.0 (0.0004)
20.9 (<0.0001)
15.0 (<0.0001)
2.8 (0.0082)
1.0 (0.189)
–7.3 (<0.0001)
7.1 (<0.0001)
6.0 (<0.0001)
–0.1 (0.9031)
0.8 (0.6052)
2.6 (0.0073)
3.8 (0.0009)
–2.9 (0.180)
–6.3 (0.0001)
–16.8 (<0.0001)
–13.3 (<0.0001)
9.8 (0.0001)
2.2 (0.3793)
2.2 (0.1812)
–6.8 (<0.0001)
–2.2 (0.0006)
–5.9 (<0.0001)
–8.8 (<0.0001)
6.7 (<0.0001)
6.9 (<0.0001)
4.8 (0.0002)
1.8 (0.3863)
6.4 (0.0034)
–3.6 (0.0044)
8.9 (<0.0001)
4.3 (0.1063)
8.5 (0.0034)
–0.6 (0.6052)
7.0 (<0.0001)
6.9 (0.0274)
10.6 (0.0028)
–5.7 (0.0585)
–0.6 (0.6052)
6.9 (<0.0001)
0.8 (0.3953)
7.7 (0.0101)
12.1 (0.0003)
0.8 (0.5223)
9.3 (<0.0001)
T0–T2
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Global health
Physical functioning
Role functioning
Social functioning
Fatigue
Pain
Diarrhoea
T0–T6
Global health
Emotional functioning
T0–T12
Global health
Emotional functioning
T0–T18
Global health
Emotional functioning
Appetite loss
T0–T24
Global health
Emotional functioning
* 90 pairwise comparisons were made for intragroup changes and p<0.0006
(0.05/90) was considered as significant.
† T0 = before treatment, TE = immediately after treatment, Tn = n months
after treatment
Study
Study design and quality
appraisal
Population
General health-related quality of life
Intergroup QLQ-C30# score changes over time
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
MeanBT/RP
95% CI
p-value‡
13.5
25.9
39.9
9.8
9.2
32.7
–31.2
–21.7
–8.5
–15.7
–19.1
–12.5
[7.5,19.6]
[20.9,30.9]
[30.7,49.1]
[3.5,16.1]
[4.0,14.4]
[24.4,40.9]
[–38.3, –24.0]
[–29.4, –14.1]
[–15.0,2.0]
[–25, –6.4]
[–25.5, –12.7]
[–19.8, –5.3]
<0.0001
<0.0001
<0.0001
0.0008
0.0001
<0.0001
<0.0001
<0.0001
0.0065
0.0002
<0.0001
0.0002
–4.0
–3.5
11.1
4.4
–1.0
5.7
3.3
[–10.0,3.0]
[–0.3,7.2]
[3.7,18.5]
[–2.7,11.6]
[–7.7,5.8]
[–1.3,12.7]
[–3.2,9.8]
0.2720
0.0812
0.0014
0.3128
0.9376
0.1340
0.4588
–7.5
3.6
[–13.9, –1.1]
[–3.5,10.5]
0.0164
0.4698
–7.9
–1.3
[–14.8, –1.0]
[–8.9,6.2]
0.0195
0.9087
–8.3
–5.6
7.9
[–16, –0.4]
[–10.9,5.6]
[1.7,14.2]
0.0377
0.7312
0.0083
–8.2
[–16.0, –0.4]
0.0379
T0–TE
Global health
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Fatigue
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
T0–T2
Global health
Physical functioning
Role functioning
Social functioning
Fatigue
Pain
Diarrhoea
T0–T6
Global health
Emotional functioning
T0–T12
Global health
Emotional functioning
T0–T18
Page 163 of 261
Global health
Emotional functioning
Appetite loss
T0–T24
Global health
Study
Study design and quality
appraisal
Population
General health-related quality of life
Emotional functioning
–2.7
[–11.4,6.0]
0.7422
Page 164 of 261
‡ Analysis of covariance (ANCOVA) for difference in QLQ-C30 changes
relative to baseline after adjusting for age, working status, PSA, Gleason
score, use of neoadjuvant hormonal therapy and pre-treatment IPSS
(International Prostate Symptom Score).
# EORTC-QLQ-30 is scored on a scale of 0–100, with higher scores
representing better HRQoL.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Ferrer et al 2008)
Prospective cohort
Multicentre, Spain
Level III-2 interventional
evidence
Accrual: April 2003 – March
2005
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 841 organ-confined prostate cancer patients
RP
EBRT
LDRBT
Age,
years
64±5.5
69.2±5.5
66.9±6.5
PSA,
ng/mL
7.9±3.3
10.1±7.9
6.9±2.3
6±1.1
5.7±4.4
Quality of life measures for men treated with LDRBT (mean±SE; higher
scores represent better health/function)*
Pre-treatment
Gleason
score
6.8±6.2
Values are mean±standard deviation
Loss to follow-up:
614 patients treated with LDRBT (275), RP (134)
and EBRT (205) were included in HRQoL analysis.
3 months
12 months
24 months
53.1±0.3
(0.07)†
52.4±0.4
(<0.001)
50.9±0.5
(<0.001)
54.7±0.5
(1.0)
56.5±0.4
(<0.001)
56.3±0.4
(0.002)
80.4±0.6
81±0.6
(1.0)
82.5±0.6
0.018
79.8±0.6
1.0
39.4±0.3
38.1±0.3
<0.001
39.5±0.3
1.0
38.9±0.3
0.663
SF-36 PCS
54±0.5
SF-36 MCS
54.3±0.4
FACT-G
FACT-P
* 6 months‘ follow-up data were reported but excluded from this analysis as
there were no significant differences from baseline at 6 months.
Quality of life measures for men treated with RP (mean±SE)‡
Pre-treatment
SF-36 PCS
54±0.5
SF-36 MCS
53.3±0.6
3 months
6 months
24 months
51.9±0.5
0.001
53±0.5
0.986
50.6±0.8
<0.001
53±0.8
1.0
53.3±0.9
1.0
54.9±0.8
0.331
Study
Study design and quality
appraisal
Population
General health-related quality of life
FACT-G
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
79.7±0.8
78±1
NR
78.9±1
NR
76.6±1.1
NR
39.8±0.4
35.6±0.5
37.9±0.4
37.2±0.5
<0.001
<0.001
<0.001
FACT-P
‡ 12 months‘ follow-up data were reported but excluded from this analysis as
there were no significant differences from baseline at 12 months.
Quality of life measures for men treated with EBRT (mean±SE)
Pre-treatment
3 months
12 months
24 months
51.4±0.5
0.089
50.9±0.5
0.007
49.2±0.6
<0.001
55.3±0.6
1.0
56.3±0.5
0.039
56.3±0.5
0.08
80±0.8
80.2±0.9
1.0
80.6±0.9
1.0
77.5±0.9
0.007
38.9±0.4
38.1±0.4
0.225
38.7±0.4
1.0
37.5±0.4
0.001
SF-36 PCS
52.5±0.5
SF-36 MCS
54.9±0.5
FACT-G
FACT-P
† p-values for change from pre-treatment value (using Bonferroni adjustment
for multiple comparisons).
PCS = physical component summary
MCS = mental component summary
NR = not reported
Page 165 of 261
(Hashine et al 2008)
Prospective cohort
Single centre, Japan
Level III-2 interventional
evidence
Accrual: January 2003 – July
2005
Downs and Black quality
score: 17/27
N: 213 (131 RP and 82 LDRBT patients)
RP
Age, years*
(range)
LDRBT p-value
68.0
70.5
0.016
(42–78) (50–85)
HRQoL at 1 month, SF-36 score*
RP
LDRBT
p-value†
Physical functioning
84.8±12.8
87.6±17.4
0.008
Role functioning
66.2±27.4
81.4±22.9
<0.001
Body pain
71.7±22.5
79.4±23.7
0.022
Study
Page 166 of 261
Study design and quality
appraisal
Population
General health-related quality of life
Overall quality assessment:
Moderate
PSA, ng/mL*
9.6
Gleason score, n :
5–6
44
7
42
8–10
36
6.7
<0.001
<0.001
51
27
4
Neoadjuvant
hormones
8
18
Nerve sparing
22
-
EBRT
-
1
General health
63.6±15.6
62.7±17.4
0.862
Vitality
58.8±20.7
69.2±19.5
0.006
Social functioning
70.1±27.5
86.1±20.4
<0.001
Role emotional
64.1±29.3
83.5±23.7
<0.001
Mental health
61.9±21.7
72.3±18.2
0.004‡
0.002
* Mean score and SD for each of the eight SF-36 components is reported at
each time point but no differences in SF-36 scores extend to 12 months;
scores range 0–100, with higher scores indicating better function/health.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
‡ Mental health component for RP was significantly worse at baseline;
therefore, it is not clear what the impact of RP is on mental health compared
with LDRBT.
* Median
† Mann-Whitney U test
(Smith et al 2010)
Prospective cohort
Population-based, NSW,
Australia
Level III-2 interventional
evidence
Accrual: October 2000 – May
2003
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 4,542 men (3,195 with histologically confirmed
T1a–2c prostate cancer and 1,347 controls with no
diagnosis of prostate cancer, as indicated and
cross-checked by registry data)
Baseline
3 years
AS
47.7±10.8
46.9±11.9
Nerve-sparing
RP
52.3±7.6
50.1±9.0
Non-nervesparing RP
50.6±8.7
48.7±9.5
1,347
EBRT
49.3±9.9
46.5±10
Combined
EBRT/ADT
46.7±11.3
44.1±11.7
LDRBT
52.6±7.9
49±9.6
Controls
49.4±9.6
47.9
All potential participants had to be physically and
mentally capable of a 30-minute telephone
interview in English.
Cases, n
Potentially
eligible
Final analysis
3,195
Unadjusted mean physical function score (score range 0–100; higher
scores indicate better function)
Controls, n
1,636
495
AS
200
NA
RP
981
NA
EBRT
123
NA
Combined
EBRT/ADT
166
NA
LDRBT
58
NA
Mean age, years
[95% CI]
61.2
61.2
[60.7, 61.7] [61, 61.5]
Unadjusted mean mental function score (score range 0–100; higher
scores indicate better function)
AS
Nerve-sparing
Baseline
3 years
51.4±9.5
53.1±9.2
Study
Study design and quality
appraisal
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Guedea et al 2009)
Prospective cohort
Single centre, Spain
Level III-2 interventional
evidence
April 2003 – March 2005
Population
General health-related quality of life
N: 304 men with prostate cancer
RP
53.6±7.7
53.3±8.5
Non-nervesparing RP
54.4±7.4
53.7±8.5
EBRT
53.1±9
52.9±9.1
Combined
EBRT/ADT
53.5±8.6
52.8±9.7
LDRBT
51.7±9.9
54±7.8
Controls
52.5±9.1
54.1
Baseline SF-36 scores‡
RP
EBRT
LDRBT
LDRBT RP
EBRT
PCS*
53.3±6
52.6±6.1
53.5±5.2
MCS†
53.7±6.2
54.1±6.2
53.7±6.9
Downs and Black quality
score: 16/27
n
56
114
143
Overall quality assessment:
Moderate
Age, years
67.5
63.9
68.8
PSA, ng/mL
6.4
7.9
11.9
Gleason score
5.7
6.3
6.4
Values are mean and n as indicated.
Change of SF-36 score at 2 years post treatment
RP
EBRT
LDRBT
PCS
–3.6±7.8
–3.3±7.1
–2.7±8.6
MCS
1.1±7.3
1.4±6.8
0.1±10.7
‡ Range 0 –100; higher scores represent better function/health.
* Physical component score
† Mental component score
Values are mean±SD unless otherwise indicated
Page 167 of 261
(Wei et al 2002)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: June 1995 – May
1999
N: 1,014 including 142 male controls who are not
further considered‡
LDRBT
Downs and Black quality
score: 16/27
n
112
Age, years
67.2±7.3
Overall quality assessment:
Moderate
Time since
primary therapy,
FACT-P scores* for follow-up exceeding one year
LDRBT
EBRT
RP
32.4†# [30.1,34.8]
36.4† [34.7,38.2]
36.9# [35.8,38.2]
* Functional Assessment of Cancer Therapy (prostate component), values
Study
Study design and quality
appraisal
Population
General health-related quality of life
months
21
are mean [99% CI].
Page 168 of 261
Adjuvant/
neoadjuvant
therapy, %
51
PSA, ng/mL
9.7±14.9
Multivariable modelling was used to adjust for age, time since therapy,
Gleason score, clinical stage, PSA and use of hormonal therapy.
Gleason score, %:
2–6
7
8–10
† # Values that share a common symbol were significantly different in a
pairwise comparison (significance set at 0.008 after Tukey adjustment for
comparisons between three groups), p<0.0005.
68.3
23.2
8.5
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
EBRT
RP
n
203
896
Age, years
70.9±7.2
63.5±7.8
Time since
primary therapy,
months
29
30
Adjuvant/
neoadjuvant
therapy, %
33
28
PSA, ng/mL
9.1±12.7
7.3±7.2
Gleason score, %:
2–6
7
8–10
43.1
47.9
9.0
59.6
37.3
3.1
Values are median±SD, except where indicated.
‡ A control group used in the primary analysis were
not considered given that a secondary analysis
made direct comparison between treatment
modalities, in accordance with inclusion criteria for
this assessment.
(Kirschner-Hermanns et al
2008)
Prospective cohort
Level III-2 interventional
N: 94 (33 LDRBT, 61 RP patients)
HRQoL after 1 year, EORTC-QLQ-30 (scale 0–100; higher scores indicate
better health/functioning)
Study
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Population
Single institution, Germany
Study design and quality
appraisal
evidence
General health-related quality of life
Accrual: January 1999 –
December 2002
Downs and Black quality
score: 15/27
Age, years†
Overall quality assessment:
Poor
PSA, ng/mL†
9.2 (1.6–55.6)
Gleason score†
5 (3–8)
OCO*
0.78 (0.08–2.67)
Max flow < 10 mL/s, %
30
Residual vol > 50 mL, %
34#
Max capacity < 200 mL, %
15
years†
67 (57–75)
PSA, ng/mL†
7.7 (3.2–17.0)
Gleason score†
5 (2–7)
OCO*
0.74 (0.34–1.70)
Max flow < 10 mL/s, %
21
Residual vol > 50 mL, %
12#
Max capacity < 200 mL, %
6
RP
64 (54–75)
LDRBT
RP
p (chi-square)
Emotional
functioning
66±30
83±19
0.005
Global HRQoL
61±17
70±20
0.024
Values are mean ±SD
LDRBT Age,
† Median (range)
* Obstruction coefficient
# Chi-square, p=0.019 (RP cf LDRBT)
Page 169 of 261
(Wyler et al 2009)
Prospective cohort
Single centre, Switzerland
Accrual:
Level III-2 interventional
evidence
BT patients, March 2001 –
December 2004
Downs and Black quality
score: 14/27
EBRT patients, January 2002 Overall quality assessment:
Poor
– December 2004
N: 212 consecutive patients with clinically localised
prostate cancer
Global health and functional scales after RP and LDRBT
5–12 months
25–36 months
37–53 months
71.7±27.4
80.6±11.4
77.8±9.6
88.9±13.6*
97.2±6.8*
88.9±19.2
93.3±9.1
Global health:
LDRBT
RP
N
70
142
Age, years
PSA,
ng/mL
61 (49–75)
6.1
(1.1–12.8)
64 (47–75)
11.3
(0.3–24)
Cognitive functioning:
Gleason score
5.7 (4–7)
6.3 (5–9)
Emotional functioning:
RP
LDRBT
RP
LDRBT
80±13.9
33.3±23.6
Study
Study design and quality
appraisal
Population
General health-related quality of life
Clinical risk*, n
Page 170 of 261
Low
Intermediate
High
39
16
0
27
24
54
* Clinical risk was low (PSA < 10 ng/mL, stage
T1c–T2a and GS < 7), intermediate (PSA 10–
20 ng/mL or stage T2b or GS =7) or high (not
defined).
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Only patients with prostate volume < 60 mL and
urinary flow rate > 10 mL/s were selected.
79% of LDRBT patients and 74% of RP patients
returned questionnaires.
RP
LDRBT
68.3±32.5
54.2±41.2
91.7±9.1
93.1±11.1
88.9±12.7
90±14.9
97.3±6
76.7±33
95.6±6.9
98.9±2.7
97.8±3.8
100±0
80±27.4
66.7±47.1
97.2±6.8
100±0
100±0
100±0
86.1±12.5
91.7±13.9
77.8±38.5
90±14.9
Physical functioning:
RP
LDRBT
Role functioning:
RP
LDRBT
Social functioning:
RP
LDRBT
76.7±25.3
58.3±35.4
* significant difference between groups
No changes in global health and function were observed within groups over
time.
Comment:
Data for 13–24 months follow-up were reported in the study but not included
here. No significant differences in scores were observed between groups at
13–24 months follow-up.
Symptom scales and single QoL items
5–12 months
25–36 months
p, within-group change‡
0
33.3±47.1
0
0
NS
0.008
6.7±14.9
33.3±47.1
5.6±13.6*
0*
NS
NS
15.6±14.9
44.4±62.9
5.6±9.3
4.6±7.4
NS
0.031
0
2.8±6.8
NS
0.037
Appetite:
RP
LDRBT
Dyspnoea:
RP
LDRBT
Fatigue:
RP
LDRBT
Nausea/vomiting :
RP
LDRBT
0†
8.3±11.8†
Study
Study design and quality
appraisal
Population
General health-related quality of life
Pain:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
RP
LDRBT
16.7±23.6
33.3±47.1
0
8.3±13.9
NS
NS
13.3±18.3
16.7±23.6
5.6±13.6
5.6±13.6
NS
NS
Insomnia:
RP
LDRBT
* Between-group comparison (Mann-Whitney U test), p=0.005
† Between-group comparison, p=0.037
‡ Kruskal-Wallis test
Data for 13–24 months and 37–53 months follow-up were reported in the
study but not included here. No significant differences in scores seen
between groups at 13–24 months or 37–53 months follow-up, or for change
from the immediately preceding periods.
Table notes:
3D-CRT = three-dimensional conformal radiotherapy; ADT = androgen deprivation therapy; LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; EORTC QLQ – C30 = European Organisation for
Research and Treatment of Cancer quality of life questionnaire; EPIC = Expanded Prostate cancer Index Composite; FACT-P = Functional Assessment of Cancer Therapy Prostate module; HRQoL = health-related
quality of life; IMRT = intensity modulated radiotherapy; NS = not significant; NA = not assessed; RP = radical prostatectomy; SF-36 = Short Form–36 health survey; UCLA-PCI = University of California, Los Angeles –
Prostate Cancer Index
Page 171 of 261
Appendix H
Page 172 of 261
Table 35
Data tables for primary and secondary
effectiveness
Studies comparing primary or secondary effectiveness outcomes for low-dose-rate brachytherapy, radical prostatectomy, external beam radiotherapy and
active surveillance for the treatment of localised prostate cancer
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study
Study design and quality
appraisal
Population
Effectiveness
(Giberti et al 2009)
Randomised controlled trial
N: 100 RP patients and 100 LDRBT patients
Freedom from biochemical recurrence at 5 years (n, %)
Single centre, Italy
Level II interventional
evidence
Questionnaires were completed for 89 RP patients
and 85 LDRBT patients (ie 11 and 15 patients were
lost to follow-up from the RP and LDRBT groups
respectively).
RP
LDRBT
p-value
81 (91)
78 (91.7)
NR
Accrual: May 1999 – October
2002
Downs and Black quality
score: 19/27
Overall quality assessment:
Moderate
Exclusion criteria were in accordance with
American Brachytherapy Society.
RP
LDRBT
No. patients
100
100
Age, years
65.2
(57–74)
65.6
(56–74)
Clinical stage
T1c (no. pts.) 64
T2a (no. pts) 36
59
41
Gleason score
5.9
5.7
PSA, ng/mL
7.8
10)
7.5 (3.5–
(2.9–9.3)
Values are mean (range) unless otherwise
indicated
(Zhou et al 2009)
Retrospective cohort
Multicentre, US
Level III-2 interventional
evidence
Accrual: January 1999 –
December 2001
N: 10,632 (more than 75% of these patients
received combined therapy or ‗no treatment‘, which
was the reference)
Downs and Black quality
score: 20/27
Overall quality assessment:
N
RP
LDRBT EBRT
936
644
876
Survival at 7 years*, percentage of patients (Kaplan-Meier)
Overall
Disease-specific
RP
89.0
97.9
LDRBT
81.0
96.6
EBRT
71.7
94.2
Moderate
Age, years, n:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
65–69
70–74
75+
562
318
56
189
312
143
178
378
320
SEER stage, n (%)
Local/regional 889
(95)
Distant/
unknown
47
(5)
595
783
(92.4) (89.4)
49
(7.6)
93
(10.6)
531
(82.5)
53
(8.2)
60
(9.3)
674
(77)
135
(15.4)
67
(7.6)
Gleason score, n (%):
<7
7–10
Unknown
714
(76.3)
177
(18.9)
45
(4.8)
Survival at 7 years* (Cox regression)
Overall survival,
hazard ratio† [95% CI]
p-value
Age (all categories)
years
1.53 [1.45–1.61]
<0.0001
Local stage
Reference
Regional stage
1.88 [1.58–2.24]
<0.0001
Reference
1.07 [0.90–1.27]
1.48 [1.22–1.79]
1.35 [1.06–1.71]
NA
0.4434
<0.0001
0.0138
Reference
0.32 [0.25–0.41]
0.40 [0.32–0.52]
0.63 [ 0.53–0.75]
0.89 [0.80–0.98]
NA
<0.0001
<0.0001
<0.0001
0.0243
Reference
0.64 [0.54–0.76]
1.16 [ 0.97–1.38]
1.83 [1.52–2.20]
NA
<0.0001
0.1101
<0.0001
Disease-specific survival,
hazard ratio† [95% CI]
p-value
Gleason score:
2–4
5–6
7–10
Unknown
Treatment:
None
RP
LDRBT
EBRT
ADT
Comorbidity:
0
–1
1
2+
Age (all categories)
1.49 [1.32–1.68]
<0.0001
Local stage
Reference
NA
Regional stage
4.06 [3.04–5.43]
<0.0001
Reference
1.53 [0.83–2.85]
4.18 [2.23–7.81]
3.41 [1.69–6.88]
NA
0.1757
<0.0001
0.0006
Gleason score:
Page 173 of 261
2–4
5–6
7–10
Unknown
Treatment:
Page 174 of 261
None
RP
LDRBT
EBRT
ADT
Reference
0.25 [0.13–0.48]
0.45 [0.23–0.87]
0.66 [ 0.41–1.04]
1.32 [1.01–1.73]
NA
<0.0001
0.0181
0.0731
0.0445
Reference
0.82 [0.56–1.20]
0.68 [ 0.43–1.06]
1.18 [0.73–1.89]
NA
0.2976
0.0895
0.4977
Comorbidity:
0
-–1
1
2+
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
* Only patients with localised disease were considered.
† Hazard ratio > 1 indicates a greater likelihood of dying, while a ratio of < 1
indicates increased likelihood of survival.
(Wong et al 2009)
Retrospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: May 1993 – July
2004
Downs and Black quality
score: 19/27
N:853 consecutive patients with localised prostate
cancer*
Five-year biochemical-free recurrence among low-risk patients who did
not have androgen deprivation therapy
LDRBT
n
225
Treatment
No. of patients
bNED (%)
3D-EBRT
109
92
197 (88)
28 (12)
IMRT
94
93
LDRBT
116
97
193 (86)
p-value
Clinical stage, n (%):
Overall quality assessment:
Moderate
T1
T2
PSA ≤ 10 ng/mL, n (%)
Gleason score ≤ 6, n (%) 173 (77)
Adjuvant hormone
treatment, n (%)
153 (68)
Low risk , n (%)
158 (70)
n
3D-EBRT
IMRT
270
314
Clinical stage, n (%):
T1
T2
PSA ≤ ng/mL,
n (%)
120 (44)
123 (46)
231 (74)
69 (22)
92 (71)
238 (76)
0.298
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Adjuvant
hormone
treatment, n (%) 47 (17)
114 (36)
Low risk , n (%) 119 (44)
109 (35)
Loss to follow-up: None evident.
* See study profile for further details.
(Beyer & Brachman 2000)
Retrospective cohort
N: 2,222 men with prostate cancer
Single centre, US
Level III-2 interventional
evidence
LDRBT
EBRT
LDRBT
n
695
1,527
5-year
7-year
5-year
7-year
p-value*
Age, years*
74
74
0–4
87
85
90
90
0.47
128 (19)
345 (50)
144 (21)
73 (10)
5 (< 1)
132 (9)
565 (37)
481 (32)
332 (22)
18 (1)
> 4–10
76
66
74
69
0.76
Accrual: December 1988 –
December 1995
Downs and Black quality
score: 18/27
Overall quality assessment:
Moderate
Freedom from biochemical recurrence (percentage of patients)
PSA, ng/mL†:
0–4
> 4–10
> 10–20
> 20
Unknown
EBRT
PSA, ng/mL
* p-value is for between-group comparison within each PSA stratum for both
time points.
Loss to follow-up: NA, results reported for all
patients on database.
* Median
† Values are n (%) for each category shown
(Pickles et al 2010)
Retrospective cohort
Multicentre, Canada
Level III-2 interventional
evidence
Accrual: July 1998 – January
2001.
N: 278 (139 LDRBT, 139 matched EBRT)
LDRBT EBRT
Page 175 of 261
Downs and Black quality
score: 17/27
Age, years
(range)
64
71
(48–79) (54–84)
Overall quality assessment:
Moderate
PSA, ng/mL
5.6
6.4
87.8
12.2
87.8
12.2
77.7
22.3
77.7
22.3
Freedom from biochemical recurrence at 5 years (percentage of patients)
LDRBT
EBRT
p (log rank)
94
100
95.2
88
78
84.7
<0.001
≤0.016
<0.001
LDRBT
EBRT
p-value
Median PSA doubling time
among patients with biochemical
recurrence, months
6
24
0.01
Prostate cancer deaths, n
1
NR
Risk group:
Low risk
Intermediate
Overall
Gleason score, %:
≤6
7
Risk group, %:
Low
Intermediate
T-stage, % (2002):
Other outcomes
1
T1a–c
T2a
T2b
Page 176 of 261
38.8
54
7.2
41.7
50.4
7.9
Percentage positive cores
≤ 50% †
87.8
87.8
ADT use, %
Mean
duration, months
31.7
30.2
6
5.8
Non-prostate cancer
deaths†, %
4
18
† 8-year projection
No PSA data during follow-up
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Radiation
dose, Gy
10
8
144
68
Values are median unless otherwise specified.
† Data available for 33% of patients
EBRT dosimetry, Gy:
< 66
66
68
> 68
(Vicini et al 2002)
Multicentre, US and Germany
Accrual: 1989–1998
Comparison of two matched
single arms
Level III-3 interventional
evidence
Downs and Black quality
score: 12/27
Overall quality assessment:
Poor
5%
23%
46%
25%
N: 6,877 men with prostate cancer of whom 5,179
are not considered for this analysis, leaving data for
1,698 patients treated with LDRBT (537), 3D-EBRT
(670) and RP (491)—see study profile for further
details
Effectiveness
Five-year outcomes (percentage of patients):
bNED
Overall survival
LDRBT
Centre 1
82
83
61–73
Median follow-up,
months
LDRBT
Centre 2
89
NR
38
3D-EBRT
85
NR
PSA, ng/mL
≤6
EBRT
71
85
5–6
RP
97
97
Age (range), years
Gleason score (range)
Table notes:
LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; RP = radical prostatectomy; IMRT = intensity modulated radiotherapy; PSA = prostate specific antigen; NA = not applicable; bNED =
biochemical freedom from recurrence; NR = not reported
0.001
Appendix I
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table 36
Data tables for economic considerations
Economic considerations of low-dose-rate brachytherapy compared with radical prostatectomy, external beam radiotherapy and active surveillance for the
treatment of localised prostate cancer
Study
Study design and quality
appraisal
Population
Cost
(Buron et al 2007)
Prospective cohort
Mean hospital costs (2001 euros)
Multicentre study, France
Level III-2 interventional
evidence
N: 435 men with low-risk prostate cancer from 11
French hospitals treated with LDRBT (308) or RP
(127)
Downs and Black quality
score: 17/27
RP
LDRBT
Age, years
62.7±6
65.2±6.3
Overall quality assessment:
Moderate
Neoadjuvant
hormones, %
6.3
43.5
IPSS
7.8
5.9
Accrual:
March 2001 – June 2002
Page 177 of 261
RP
LDRBT
Mean
difference
Consumables
410
[288,533]
5,192
[5025,5360]
4,782*
[4510,5054]
Operating
theatre
1,674
[1602,1745]
752
[642,863]
–922*
[–1099,–744]
Values are mean±standard deviation.
Hospitalisations
Loss to follow-up after 24 months was between
35% and 59% (N data not provided) depending on
treatment arm—see study profile for further details.
4,387
[4150,4625]
1,060
[1011,1110]
–3,327*
[–3497,–3157]
Post-operative CT
†
155
†
Total
6,472
[6206,6737]
7,159
[6939,7380]
687*
[305,1071]
2 months
387
[76,699]
47
[0,93]
–340*
[–552,–129]
6 months
610
[247,972]
64
[14,114]
–546*
[–790,–302]
12 months
775
[386,1164]
88
[32,145]
–687*
[–950,–424]
18 months
874
[477,1271]
246
[73,421]
–628*
[–998,–258]
24 months
992
[565,1418]
268
[93,443]
–724*
[–1108,–340]
6,859
[6403,7315]
7,206
[6973,7438]
347
[117,811]
Values are mean±standard deviation, unless
otherwise specified
Initial treatment costs:
Hospital follow-up costs:
Hospital costs:
2 months
Study
Study design and quality
appraisal
Population
Cost
Page 178 of 261
6 months
7,081
[6577,7586]
7,223
[6990,7457]
142
[–343,627]
12 months
7,247
[6717,7777]
7,346
[6818,7873]
7,248
[7014,7481]
7,406
[7123,7688]
1
[–495,497]
60
[–493,613]
7,463
[6916,8010]
7,427
[7144,7710]
–36
[–597,525]
RP
LDRBT
Mean
difference
2 months
118
[93,144]
243
[219,267]
125*
[83,167]
6 months
224
[178,269]
290
[264,316]
66*
[15,118]
12 months
289
[233,346]
346
[315,377]
57
[5,118]
18 months
356
[289,423]
420
[378,461]
64
[–15,144]
24 months
419
[343,494]
482
[435,528]
63
[–29,152]
18 months
24 months
Mean outpatient costs (2001 euros)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Mean costs due to loss of productivity in working patients (2001 euros)
RP
LDRBT
Mean
difference
2 months
2,012
[1368,2656]
487
[105,869]
–1,525*
[–2213,–837]
6 months
2,667
[1710,3625]
568
[112,1023]
–2,099*
[–3024,–1175]
12 months
3,514
[1810,5217]
588
[123,1053]
–2,926*
[–4319,–1532]
18 months‡
3,514
[1810,5217]
588
[123,1053]
–2,926*
[–4319,–1532]
Study
Study design and quality
appraisal
Population
Cost
24 months
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
3,678
[1774,5581]
620
[153,1086]
–3,058
[–4586,–1530]
RP
LDRBT
Mean
difference
2 months
7,465
[6966,7964]
7,525
[7264,7785]
60
[–455,575]
6 months
7,930
[7304,8555]
7,616
[7349,7882]
–314
[–888,261]
12 months
8,353
[7612,9093]
7,702
[7432,7971]
–651
[–1282,20]
18 months
8,506
[7771,9242]
7,929
[7616,8243]
–577
[–1253,99]
24 months
8,715
[7933,9496]
8,019
[7704,8334]
–696
[–1394,2]
Mean societal costs (2001 euros)
* Statistically significant difference
† Reason for missing data unclear.
‡ Not clear why these results are identical to 12-month results— possibility of
error in reporting.
(Ciezki et al 2000)
Prospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual:
January 1997 – October 1998
Downs and Black quality
score: 17/27
Overall quality assessment:
Moderate
N: 583 consecutive men with clinically localised
prostate cancer underwent retropubic RP (404) or
LDRBT (179)
Tumour grade, clinical stage, preoperative PSA,
age and comorbidity were evenly distributed
between the groups.
Page 179 of 261
Majority of patients had PSA < 10 ng/mL, Gleason
score ≤ 6 and stage T1 or T2a disease.
Categorical technical costs for RP vs LDRBT (relative cost ratios)
RP
LDRBT (pre-plan)
LDRBT (real-time)
1.0
1.0
1.0
0.44
0.01
0.11
0.56
0.01
0.13
1.0
1.0
1.0
0.49
0.07
17.1
0.67
0.13
13.8
Category:
Anaesthesiology
Laboratory medicine
Pharmacy
Operating room
nursing
Floor nursing
Radiology
Study
Study design and quality
appraisal
Population
Cost
Total costs for RP vs LDRBT (relative cost ratios)
Page 180 of 261
RP
LDRBT (pre-plan) LDRBT (real-time)
1.0
1.0
0.36
2.16
0.42
2.58
Professional cost
1.0
0.97
1.02
Total cost
1.0
1.85
2.05
Category:
Technical cost
Excluding seeds
Including seeds
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Kohan et al 2000)
Prospective cohort
Single centre, US
Level III-2 interventional
evidence
Accrual: June 1995 –
September 1996
Downs and Black quality
score: 15/27
Overall quality assessment:
Poor
N: 60 consecutive men with clinically localised
prostate cancer (T1–T2, N0, M0) underwent RP
(38) and LDRBT with 125I (13) or 103Pd (9)
RP
LDRBT
Age, years
(range)
61.2
(43–71)
71.1
(60–86)
PSA, ng/mL
8.4 (2.2–34)
34)
12 (2.2–
(2.3–37.7)
6 (4–8)
6 (4–8)
Gleason
score
Charge comparison for RP and LDRBT (US$)
Pre-operative charges
Operative charges
RP
LDRBT
1,526.20
1,801.20
11,352.59
Post-operative charges
1,007.20
Total charges
13,904.60
9,818.17*
2,285.20*
13,886
* p<0.05
Charge comparison for LDRBT (US$)
125I
103Pd
Pre-operative charges
1,154.65
2,735.18†
Post-operative charges
2,548.50
1,904.79
† p<0.01
Data were stratified by radioactive source; however, no statistical analysis
was performed comparing cost of 125I LDRBT with RP and therefore
conclusions regarding the cost-efficacy of 125I LDRBT compared to RP are
Study
Study design and quality
appraisal
Population
Cost
difficult.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Conclusions are further inhibited due to the bias inherent in charge variation
between institutions and the age of the data collected during 1995–96.
(Ollendorf et al 2009a)
Health technology
assessment, US
Patient accrual is varied (HTA
is based on three separate
systematic reviews).
Included studies were
published between January
1996 – May 2009 for RP and
AS; 1995 – August 2008 for
IMRT; and 1995 – August
2008 for LDRBT (the LDRBT
systematic review also
updated the IMRT review).
Health technology
assessment (HTA)
Level of evidence for this
HTA cannot be assessed.
The systematic reviews on
which the HTA is based rely
primarily on noncomparative evidence (level
IV).
Quality: good (Drummond &
Jefferson 1996)
Adverse event rates
Cost–utility analysis
The HTA used adverse event rates from systematic
reviews, which required included studies to contain
‗a preponderance‘ of patients of clinical stage T1–
T2a, Gleason score ≤ 6 and PSA < 10 ng/mL.
Comparison of LDRBT, IMRT, AS and RP
Base case presented in the text—see Table 13.
However, studies including intermediate-risk
patients were not excluded.
Baseline adverse event rates were taken from
Bacon et al (2003) and Andersson et al (2004).
Patient utilities
Dale et al (2008); Stewart et al (2005); Sullivan &
Ghushchyan (2006)
Transition probabilities
Alibhai et al (2003); D‘Amico et al (1999); Horwitz
et al (2005)
Costs
US Medicare and other sources
Table notes:
AS = active surveillance; LDRBT = low-dose-rate brachytherapy; EBRT = external beam radiotherapy; HTA = health technology assessment; IMRT = intensity modulated radiotherapy; PSA = prostate specific antigen;
QALY = quality adjusted life year; RP = radical prostatectomy
Page 181 of 261
Appendix J
Studies included in the review
Page 182 of 261
Profiles of included studies on safety and effectiveness
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
(Giberti et al 2009)
Level II
interventional
evidence
Randomised
controlled trial
N: 100 RP patients and 100 LDRBT patients
Intervention: LDRBT
with D90 > 140 Gy
considered the cut-off
to predict good-quality
implant
Safety
5 years
Single centre, Italy
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Accrual: May 1999
– October 2002
Downs and Black
quality score: 19/27
Overall quality
assessment:
Moderate
Questionnaires were completed for 89 RP
patients and 85 LDRBT patients (ie 11 and 15
patients were lost to follow-up from the RP
and LDRBT groups respectively).
Exclusion criteria were in accordance with
American Brachytherapy Society.
RP
LDRBT
No. patients
100
100
Age, years
(range)
65.2
(57–74)
65.6
(56–74)
64
36
59
41
Gleason score
5.9
5.7
PSA, ng/mL
7.8
10)
7.5 (3.5–
(2.9–9.3)
Comparator: RP with
bilateral nerve sparing
performed for all
patients
Urinary, bowel and sexual function
Urinary and erectile function were assessed using
IPSS and IIEF-5 questionnaires.
Urinary and bowel symptoms, sexual function and
activity were measured using relevant domains of
EORTC-QLQ and PR25.
General HRQoL
General QoL was assessed using EORTC-QLQ.
Clinical stage:
T1c (no. pts)
T2a (no. pts)
Values are mean (range) unless otherwise
indicated.
(Lee et al 2001)
Single institution,
US.
Accrual: May 1998
– June 1999
Level III-2
interventional
evidence
Downs and Black
quality score: 22/27
Overall quality
assessment:
Prospective cohort
N: 90
Intervention:
Safety
All patients treated between May 1998 and
June 1999 (n=98) were offered enrolment. 90
patients (91%) agreed to complete the FACTP and IPSS questionnaires.
2-stage (pre-operative
planning) 125I LDRBT,
prescribed to 144 Gy
(TG43)
General HRQoL
LDRBT
Comparators:
10 MV photon 3D-CRT
FACT-P was collected and compared between
treatment groups at baseline, 1 month, 3 months
and 12 months.
1 year
Author & year,
location and
accrual period
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Level of evidence
and quality
assessment
Moderate
Study design
Study population
(inclusion/exclusion criteria)
Intervention
N
44
Age, years
67.1 (49–79)
prescribed to 70.2 –
72 Gy to 95% of the
volume in 1.8 Gy
fractions using a fourfield technique.
Stage, n (%)
T1
T2
26 (59)
18 (41)
PSA, ng/mL
6.5 (1.3–13.5)
Gleason score n (%)
≤6
7
>7
38 (86)†
6 (14)
0 (0)
EBRT
N
23
Age, years
68.8 (51–79)
Stage, n (%):
T1
T2
PSA, ng/mL
12 (52)
11 (48)
8.1 (2.9–19.6)
Gleason score n (%)
≤6
7
>7
11 (48)
10 (43)
2 (9)
RP
N
23
Age, years
61.0 (42–68)*
Page 183 of 261
Stage, n (%)
T1
T2
PSA, ng/mL
19 (83)
4 (17)
6.2 (1.3–12.0)
Retropubic
prostatectomy with
nerve sparing
performed at the
discretion of the
operating surgeon.
Pelvic lymph dissection
was routinely
performed.
Outcomes assessed (relevant to this review)
Duration of
follow-up
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention:
Effectiveness
7 years
LDRBT
Kaplan-Meier overall and disease-specific survival
at 7 years post treatment
Page 184 of 261
Gleason score n (%)
16 (70)
5 (22)
2 (9)
≤6
7
>7
Values are median (range) or n (%)
† significantly more Gleason ≤ 6 than RP or
EBRT (p=0.015); * significantly younger than
LDRBT or EBRT (p=0.0006).
(Zhou et al 2009)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Multicentre, US
Accrual: January
1999 – December
2001
Level III-2
interventional
evidence
Retrospective
cohort
N: 10,632 (more than 75% of these patients
received combined therapy or ‗no treatment‘,
which was the reference)
Downs and Black
quality score: 20/27
Overall quality
assessment:
Moderate
RP
LDRBT EBRT
936
644
876
65–69
562
189
178
70–74
318
312
378
75+
56
143
320
N
Age, n, years:
SEER stage, n (%):
Local/regional 889
(95)
Distant/
unknown
47
(5)
595
783
(92.4) (89.4)
49
(7.6)
93
(10.6)
531
(82.5)
53
(8.2)
60
(9.3)
674
(77)
135
(15.4)
67
(7.6)
Gleason score, n (%):
<7
7–10
Unknown
714
(76.3)
177
(18.9)
45
(4.8)
All categories vary significantly with treatment
(chi-square p<0.001)
Comparators:
RP and EBRT
Treatment details are
not provided and are
likely to vary between
centres.
Cox regression analyses of overall and disease
specific survival controlling for age, race, tumour
stage, Gleason score, pre-treatment comorbidity
and treatment
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
with prescription dose
of 145 Gy using realtime planning
Safety
Mean,
months
453 patients excluded because they were
diagnosed with prostate cancer on or after
their date of death, leaving 10,179 patients.
Only 2,456 patients were treated with RP,
LDRBT or EBRT monotherapy.
Eligibility of other patient groups for this
analysis is uncertain.
Population defined as all men aged 65 years
or older residing in Ohio, diagnosed with
incident prostate cancer during 1999–2001.
(Eade et al 2008)
Single centre, US
Accrual:
LDRBT patients,
May 1998 – August
2004
EBRT patients,
August 2001 –
June 2004
Level III-2
interventional
evidence
Prospective cohort
Downs and Black
quality score: 19/27
Overall quality
assessment:
Moderate
N: 374 low-risk prostate cancer patients (as
defined by American Joint Committee on
Cancer) with Gleason score < 7
EBRT
LDRBT
N
216
158
Age,
years
67.6 (27–81)*
64.7 (42–78)
PSA,
ng/mL 5.2 (0.4–9.6)
5.2 (0.5–9.8)
* Values are median (range)
Clinical stage, n (%):
T1c
T2a
T2b
169 (78.2)
33 (15.3)
14 (6.5)
134 (83.5)
26 (16.5)
0
No patients were lost to follow-up.
(Wong et al 2009)
Single centre, US
Page 185 of 261
Accrual: May 1993
– July 2004
Level III-2
interventional
evidence
Downs and Black
quality score: 19/27
Overall quality
assessment:
Retrospective
cohort
N:853 consecutive patients with localised
prostate cancer*
LDRBT
n
225
Clinical stage, n(%):
T1
197 (88)
Acute and late gastrointestinal and genitourinary
side effects were recorded using modified
Radiation Therapy Oncology Group RTOG scale.
Number of urethral strictures were also recorded.
LDRBT: 48
EBRT: 43
Comparator: EBRT
with prescription dose
of 74–78 Gy delivered
in daily fractions of
2.0 Gy; rectal volume
receiving > 65 Gy and
> 40 Gy limited to
< 7% and < 35%
respectively; bladder
volume receiving
> 65 Gy and > 40 Gy
limited to < 25% and
< 50% respectively
Intervention: Preplanned LDRBT using
either iodine
(peripheral dosage of
144 Gy) or palladium
(120 Gy)
Safety
106 patients in total
received monotherapy
Five-year disease-free recurrence was calculated
using the Kaplan-Meier product limit method.
Acute and Late RTOG gastrointestinal and
genitourinary side effects (maximum score at any
time following treatment)
Effectiveness
Median,
months
LDRBT, 58
3D-EBRT,
62
IMRT, 56
Author & year,
location and
accrual period
Page 186 of 261
Level of evidence
and quality
assessment
Moderate
Study design
Study population
(inclusion/exclusion criteria)
T2
T3
Intervention
28 (12)
0
with iodine and their
unknown distribution
among the risk groups
makes it uncertain
(however probable) if
the majority of low-risk
patients received
iodine implants.
PSA, ng/mL, n (%):
193 (86)
28 (12)
4 (2)
≤ 10
10.1–20
> 20
Gleason score, n (%):
173 (77)
52 (23)
≤6
≥7
Comparators:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Adjuvant hormone
treatment, n (%):
No
Yes
3D conformal EBRT at
a median prostate
dosage of 68.4 Gy
delivered daily
fractions of 1.8–2.0.
153 (68)
72 (32)
Risk group, n (%):
Low
Intermediate
High
n
Intensity modulated
EBRT at a median
prostate dosage of
75.6 Gy
158 (70)
58 (26)
9 (4)
3D-EBRT
IMRT
270
314
120 (44)
123 (46)
27 (10)
231 (74)
69 (22)
14 (4)
Clinical stage,
n (%):
T1
T2
T3
PSA, ng/mL, n (%):
≤ 10
10.1–20
≥ 20
192 (71)
52 (19)
26 (10)
238 (76)
54 (17)
22 (7)
Adjuvant hormone
treatment, n (%):
No
Yes
223 (83)
47 (17)
200 (64)
114 (36)
Outcomes assessed (relevant to this review)
Duration of
follow-up
lDRBT, 49
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
with a prescribed dose
of either 160 Gy or
120 Gy, depending on
whether iodine or
palladium seeds were
used—663 (95%) and
32 (5%) patients
respectively
All cases were
undertaken prior to
TG43 guidelines.
Effectiveness
Median,
months
Risk group, n (%):
Low
Intermediate
High
119 (44)
111 (41)
40 (15)
109 (35)
151 (48)
54 (17)
Loss to follow-up: None evident.
* Only patients with low-risk disease (stage
T1–T2, PSA ≤ 10 ng/mL, Gleason score ≤ 6)
were considered eligible and, of these, only
those who did not receive androgen
deprivation therapy had results for which
relevant data could be extracted.
Results for patients who received combination
EBRT and LDRBT (n=44) were not
considered.
(Beyer & Brachman
2000)
Single centre, US
Accrual: December
1988 – December
1995
Level III-2
interventional
evidence
Downs and Black
quality score: 18/27
Overall quality
assessment:
Moderate
Retrospective
cohort
N: 2,222 men with prostate cancer
Page 187 of 261
LDRBT
EBRT
n
695
1527
Age, years*
74
74
128 (19)
345 (50)
144 (21)
73 (10)
5 (< 1)
132 (9)
565 (37)
481 (32)
332 (22)
18 (1)
145 (21)
433 (63)
85 (13)
20 (3)
12 (2)
434 (28)
705 (46)
268 (18)
116 (8)
5 (< 1)
117 (17)
290 (19)
PSA, ng/mL†:
0–4
> 4–10
> 10–20
> 20
Unknown
Gleason score†:
2–4
5–6
7
8–10
Unknown
Clinical stage†:
T1
Comparator: EBRT at
median dose of 66.6
(range 14.4–72.0) Gy
5- and 7-year biochemical free recurrence was
reported according to PSA category, as indicated in
the ‗Study population‘ column.
Only outcomes for patients with PSA ≤ 10 ng/mL
are considered.
LDRBT:
41.3
EBRT: 51.3
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Page 188 of 261
T2
578 (83)
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention:
Safety
LDRBT monotherapy
Bowel function and bowel bother following
treatment (every 3–6 months) measured by the
University of California and Los Angeles (UCLA)
Prostate Cancer Index (PCI)
Mean,
months
1238 (81)
Loss to follow-up: NA, results reported for all
patients on database.
* Median
† Values are n (%) for each category shown.
(Litwin et al 2004)
Multicentre, US
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Accrual period is
not reported.
Level III-2
interventional
evidence
Downs and Black
quality score: 18/27
Overall quality
assessment:
Moderate
Prospective cohort
study
N: 1,584 consecutively recruited patients from
31 community- and academic-based urology
practices
All patients must have consented, and have
been treated with RP, EBRT or LDRBT within
the first 6 months of diagnosis.
RP (n=1,276)
Age, years
61.2±6.8
Follow-up, months
14.3±8.2
Time to 1st assessment
months
3.5±2.8
Gleason score, %:
2–6
7
8–10
78
19
4
Clinical stage, %:
cT1
cT2
cT3
42
55
2
EBRT (n=99)
Age, years
70.9±6.1
Follow-up, months
16.1±8.4
Time to 1st assessment,
months
2.8±2.2
Gleason score, %:
Comparators:
RP and EBRT
RP:
14.3±8.2
EBRT:
16.1±8.4
LDRBT:
13.4±7.7
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
2–6
7
8–10
Page 189 of 261
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
with prescribed dose of
145 Gy and mean
rectal volume of 1.4 cc
receiving 145 Gy; 243
patients treated using
real-time planning
while the remaining 65
underwent preplanning
Safety
Mean,
months
67
25
8
Clinical stage, %:
cT1 (%)
cT2 (%)
cT3 (%)
44
52
3
LDRBT (n=209)
Age, years
68.6±7.4
Follow-up, months
13.4±7.7
Time to 1st assessment
months
4.2±3.1
Gleason score, %:
2–6
7
8–10
89
9
1
Clinical stage, %:
cT1 (%)
cT2 (%)
cT3 (%)
43
57
0
Values are mean±SD unless otherwise
specified.
(Buron, Le Vu et al.
2007)
Level III-2
Multicentre, France
Reporting 8/11
Quality:
Prospective cohort
N: 435 men with low-risk prostate cancer from
11 French hospitals treated with LDRBT (308)
or RP (127)
RP
LDRBT
Age, years
62.7±6
65.2±6.3
Confounding 3/6
Neoadjuvant
hormones, %
6.3
43.5
Total 16/27
Clinical stage, %:
Accrual:
Ex Valid 1/3
March 2001 – June
2002
Bias 4/7
Urinary, bowel and sexual function
Outcomes were assessed using European
Organization for Research and Treatment of
Cancer Quality of Life Questionnaire (EORTC
QLQ) prostate cancer specific (PR-25) module.
Outcomes were obtained at seven time points
during follow-up: pre-treatment, immediate posttreatment, and 2, 6, 12, 18 and 24 months following
LDRBT:
25.8
RP: 25
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Page 190 of 261
T1
T2
Intervention
52.8
47.2
64.8
35.2
PSA,
ng/mL
8.9±4
7.5±2.7
Gleason score
5.9±1.1
5.5±1.1
IPSS
7.8
5.9
Outcomes assessed (relevant to this review)
Duration of
follow-up
treatment.
Comparator: RP
(retropubic)
General HRQoL
EORTC-QLQ was used to assess general QoL
outcomes before and after treatment at each of the
study follow-up points.
Response
rate, %:
Cost
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Before
treatment
Immediately
after treatment
2 months
6 months
12 months
18 months
24 months
89
94
70
72
57
47
39
41
85
85
78
63
60
65
Initial treatment, hospital follow-up, outpatient and
production loss costs were prospectively collected
and analysed.
Values are mean±standard deviation, unless
otherwise specified.
(Ciezki et al 2000)
Single centre, US
Accrual:
January 1997 –
October 1998
(Ferrer et al 2008)
Multicentre, Spain
Accrual: April 2003
– March 2005
Level III-2
interventional
evidence
Prospective cohort
Downs and Black
quality score: 17/27
Tumour grade, clinical stage, preoperative
PSA, age and comorbidity were evenly
distributed between the groups.
Overall quality
assessment:
Moderate
Level III-2
interventional
evidence
Downs and Black
quality score: 17/27
N: 583 consecutive men with clinically
localised prostate cancer underwent
retropubic RP (404) or LDRBT (179).
Intervention: LDRBT
with either real-time or
pre-planning
techniques
Cost
NA
Technical and professional (perioperative) costs
from a hospital-wide accounting system were used
to generate cost ratios for a comparison of LDRBT
(real-time and pre-planning procedures) and RP.
Comparator: RP
(retropubic)
Majority of patients had PSA < 10 ng/mL,
Gleason score ≤ 6 and stage T1 or T2a
disease.
Prospective cohort
N: 841 organ-confined prostate cancer
patients
Age,
years
RP
EBRT
LDRBT
64±5.5
69.2±5.5 66.9±6.5
Intervention: LDRBT
with prescription dose
of 144 Gy according to
TG43
Safety
Urinary, bowel and sexual function
HRQoL questionnaires* were administered before
and after (1,3, 6, 12 and 24 months) treatment
* Expanded Prostate Cancer Index Composite
2 years
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Overall quality
assessment:
Moderate
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
PSA,
ng/mL
Comparators:
7.9±3.3
10.1±7.9 6.9±2.3
(EPIC) and the American Urological Association
Symptom Index (AUA)
Gleason
score
6.8±6.2
6±1.1
5.7±4.4
Values are mean±standard deviation.
Clinical stage, n (%):
T1
T2
Tx
88
(65.7)
46
(34.3)
0
106
(51.7)
95
(46.3)
4 (2)
224
(81.5)
51
(18.5)
0
98
(47.8)
70
(34.1)
37
(18)
241
(87.6)
32
(11.6)
2
(0.7)
EBRT using 3D
conformal technique
with mean dose of
74 Gy in 1.8–2.0 Gy
daily fractions
RP with some cases of
nerve sparing at the
discretion of the
operating surgeon
Risk group*, n (%):
Low
58
(43.3)
Intermed. 71
(53)
High
5
(3.7)
Duration of
follow-up
General HRQoL
General QoL and non-prostate (general) cancer
specific outcomes were obtained using Functional
Assessment of Cancer Therapy (FACT-G) and the
Medical Outcomes Study 36-Item Short Form (SF36).
FACT-P (prostate-specific items) data were
collected and are included under general QoL for
this assessment since scores could not be split into
urinary, bowel, and sexual components.
Loss to follow-up:
614 patients treated with LDRBT (275), RP
(134) and EBRT (205) were included in
HRQoL analysis.
* Risk groups: Low (T1c or T2a, PSA
< 10 ng/mL and Gleason score < 6),
intermediate (Intermediate; T2b, PSA 11–
20 ng/mL, or Gleason score = 7) and high
(T2c, PSA > 20 ng/mL or Gleason score > 7)
Only outcomes for low-risk patients were
considered for the purposes of this
assessment.
Page 191 of 261
(Hashine et al
2008)
Single centre,
Japan
Level III-2
interventional
evidence
Downs and Black
quality score: 17/27
Prospective cohort
N: 213 (131 RP and 82 LDRBT patients)
Intervention:
Safety
Urinary function
122 respondents in RP arm, patient
characteristics only provided for responders
Two-stage (preoperative planning) 125I
LDRBT, prescribed to
145 Gy
Functional outcomes as measured using the
University of California and Los Angeles (UCLA)
1 year
Page 192 of 261
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Accrual: January
2003 – July 2005
Overall quality
assessment:
Moderate
Study design
Study population
(inclusion/exclusion criteria)
RP
Age, years*
(range)
LDRBT p-value
68.0
70.5
0.016
(42–78) (50–85)
Clinical stage, n:
T1
T2
T3
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
PSA, ng/mL*
0.008
79
33
10
66
16
0
9.6
6.7
Gleason score, n:
5–6
7
8–10
Intervention
Comparator:
Retropubic RP as
described by Walsh
performed by two
urologists
51
27
4
Neoadjuvant
hormones
8
18
Nerve sparing
22
-
EBRT
-
1
Duration of
follow-up
Prostate Cancer Index (PCI) at baseline and 1, 3, 6
and 12 months following treatment.
UCLA-PCI measures urological, bowel and sexual
function outcomes, and the bother associated with
each outcome.
General HRQoL
Quality of life outcomes as measured by the
medical outcomes study Short Form (SF-36).
SF-36 measures HRQoL in eight domains: physical
functioning, role physical, body pain, general
health, vitality, social functioning, role emotional
and mental health. Outcomes were measured at
baseline, 1, 3, 6 and 12 months.
<0.001
<0.001
44
42
36
Outcomes assessed (relevant to this review)
0.002
*Median
(Pickles et al 2010)
Multicentre,
Canada
Accrual: July 1998
– January 2001.
Level III-2
interventional
evidence
Downs and Black
quality score: 17/27
Overall quality
assessment:
Moderate
Retrospective
cohort
N: 278 (139 LDRBT, 139 matched EBRT)
LDRBT EBRT
Age, years
(range)
64
71
(48–79) (54–84)
PSA, ng/mL
5.6
6.4
87.8
12.2
87.8
12.2
77.7
22.3
77.7
22.3
Gleason score, %:
≤6
7
Risk group, %:
Low
Intermediate
Intervention:
Effectiveness
One-stage (intraoperative planning) 125I
LDRBT planned to a
minimum peripheral
dose of 144 Gy with
post-implant dosimetry
at day 30.
Freedom from biochemical recurrence (defined by
the Phoenix definition)
Patients with Gleason
7 or Gleason 6 and
PSA > 10 and ≤ 15
were given ADT
3 months before
implant continuing for
3 months following
The use of ADT following treatment (not continuing
adjuvant therapy) was also measured as a
surrogate for progressing disease.
Quality assurance was used to ensure a true
recurrence rather than a PSA ‗bounce‘.
Overall survival and prostate cancer specific
survival were assessed.
Safety
Late treatment side effects (urinary and bowel side
effects) were measured using the Radiation
Median,
months
LDRBT: 68
EBRT: 67
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Clinical stage, % (2002):
implant.
Therapy Oncology Group (RTOG) toxicity scale.
Patients with large
prostate glands
(> 40 cc in the first
year of the study and
> 50 cc thereafter)
were also given
6 months of ADT as
above.
Late side effects are defined as those occurring at
least 1 year from LDRBT implant or at least
6 months following the end of EBRT treatment.
T1a–c
T2a
T2b
38.8
54
7.2
41.7
50.4
7.9
≤ 50% †
87.8
87.8
ADT use, %
31.7
30.2
6
5.8
Per cent positive cores
Mean
duration (months)
Comparator:
No PSA data during follow-up
Radiation
dose, Gy
10
8
144
68
Values are median unless otherwise specified.
† Data available for 33% of patients
EBRT dosimetry:
< 66 Gy
66 Gy
68 Gy
> 68 Gy
5%
23%
46%
25%
Page 193 of 261
All patients were treated between 1998 and
2001, and were matched on PSA level (within
1 ng/mL), same Gleason category (≤ 6 or 7),
clinical stage (T1 or T2), same percentage
positive biopsy cores (when available, > or
≤ 50%), and the same use and duration of
ADT (No or Yes, duration within 3 months).
When matches could not be obtained, patients
were discarded from the analysis.
Matching occurred without knowledge of
3D-Conformal
radiotherapy treated to
doses in the range
52.5–72.0 Gy (five
patients received
52.5 Gy in 20
fractions).
Duration of
follow-up
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention:
Safety
3 years
AS, RP, EBRT,
LDRBT, ADT,
combined EBRT/ADT
Telephone interview conducted to assess:
Page 194 of 261
patient outcome (and was facilitated by
database software).
Eligibility for LDRBT was more stringent and
therefore LDRBT criteria were applied to
EBRT patients.
394 treated with LDRBT.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
1,369 treated with EBRT, 667 entered onto
the EBRT database, 207 met the eligibility
criteria.
139 LDRBT patients successfully matched 1:1
with EBRT patients.
(Smith et al 2010)
Population-based,
NSW, Australia
Level III-2
interventional
evidence
Accrual: October
2000 – May 2003
Downs and Black
quality score: 17/27
Overall quality
assessment:
Moderate
Prospective cohort
N: 4,542 men (3,195 with histologically
confirmed T1a–2c prostate cancer plus 1,347
controls with no diagnosis of prostate cancer,
as indicated and cross-checked by registry
data)
All potential participants had to be physically
and mentally capable of a 30-minute
telephone interview in English.
Cases, n
Controls, n
Potentially
eligible
3,195
1,347
Final analysis
1,636
495
200
NA
AS
RP
981
EBRT
123
NA
Combined
EBRT/ADT
166
LDRBT
58
NA
Mean age,
years
61.2
61.2
NA
NA
Comparator:
Follow-up of healthy
controls, matched by
age and residence
from the NSW electoral
role
Urinary, bowel and sexual function
HRQoL measured using domain-specific items for
urinary, bowel and sexual function according to the
long form University of California, Los Angeles
(UCLA) prostate cancer index (adapted).
General HRQoL
Physical and mental component scores were also
collected using the UCLA prostate cancer index
(adapted).
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
[95% CI]
(Frank et al 2007)
Single centre, US
Accrual: 1998 –
2000
Level III-2
interventional
evidence
Retrospective
cohort
Downs and Black
quality score: 16/27
[60.7, 61.7]
LDRBT RP
EBRT
64
68
Loss to
follow-up, n (%) 86
(54)
Overall quality
assessment:
Moderate
61
166
(41)
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
with prescribed dose of
145 Gy
Safety
Median,
years
HRQoL measured using mailed Extended Prostate
Index Composite (EPIC) surveys
LDRBT: 3.5
Comparators:
Retrospective analysis meant that no baseline
HRQoL data were available for comparison with
post-treatment data, and only a one-point-in-time
between-group comparison was made.
EBRT: 4.7
24 months
[61, 61.5]
N: 960 men treated with LDRBT (160), RP
(400) and HDR EBRT (400)
Age, years*
Intervention
265
(66)
* Values are median
Only patients treated with monotherapy were
eligible for inclusion
EBRT with prescribed
dose of 78 Gy
RP with some cases of
nerve sparing at
surgeon discretion
Urinary, bowel and sexual function
RP: 4
97% of patients had T1–2 disease and
Gleason score < 7
(Guedea et al
2009)
Single centre,
Spain
April 2003 – March
2005
Level III-2
interventional
evidence
Downs and Black
quality score: 16/27
Overall quality
assessment:
Moderate
Prospective cohort
N: 304
Intervention:
Safety
No patients were reported as being lost to
follow-up.
125I
Expanded Prostate Cancer Index Composite
(EPIC) urinary, bowel, sexual and hormonal
function
Varying numbers of valid quality of life
questionnaires are reported at each time
point.
LDRBT
n
56
Age, years
67.5±5.9
PSA, ng/mL
6.4±1.5
Gleason score
5.7±0.6
Stage, n (%):
Page 195 of 261
T1
T2
Tx
50 (89.3)
6 (10.7)
0 (0)
Risk category, n (%):
Low
Intermediate
High
55 (98.2)
1 (1.8)
0 (0)
LDRBT (without
EBRT) to 144 Gy to
the reference isodose
(100%) as
recommended by
TG43
Comparators:
External beam 3D
conformal radiotherapy
to a mean dose of
74.4 Gy (SD 4.2)
RP with nerve sparing
used in low-risk
patients when feasible.
Medical Outcomes Study 36-Item Short Form (SF36) physical and mental component summaries
(PCS and MCS)
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Page 196 of 261
Neoadjuvant
hormones, (%)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention:
Safety
BT performed via
transperineal route
with TRUS guidance at
Urinary, Bowel and Sexual Function
Median, 2
years
11 (19.7)
RP
EBRT
n
114
143
Age, years
63.9 (5.8)
68.8 (5.7)
PSA, ng/mL
7.9±3.3
11.9±9.2
Gleason score
6.3±0.8
6.4±1
74 (64.9)
40 (35.1)
0 (0)
56 (41.8)
76 (56.7)
2 (1.5)
Stage, n (%):
T1
T2
Tx
Risk category, n (%):
Low
Intermediate
High
49 (43)
60 (52.6)
5 (4.4)
Neoadjuvant
hormones, n (%) 6 (5.3)
34 (25.4)
63 (47)
37 (27.6)
53 (39.6)
Risk definitions:
Low = T1c or T2a and PSA ≤ 10 and Gleason
≤6
Intermediate = low risk but with T2b, or PSA =
11–20 or Gleason = 7
High = any of T2c or PSA > 20 or Gleason 8–
10
Values are mean±SD unless otherwise
specified.
(Wei et al 2002)
Single centre, US
Accrual: June 1995
Level III-2
interventional
evidence
Downs and Black
Retrospective
cohort
N: 1,014 including 142 male controls who are
not further considered‡
LDRBT
Summary scores from the EPIC* questionnaire
were reported for urinary irritation, urinary
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Author & year,
location and
accrual period
– May 1999
Level of evidence
and quality
assessment
quality score: 16/27
Overall quality
assessment:
Moderate
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
n
112
Response rate, %
73.7
prescribed dose of 160
Gy
incontinence, bowel and sexual function for followup exceeding 1 year
Age, years
67.2±7.3
General HRQoL
Time since primary
therapy, months
21
A subset of patients
(unknown proportion)
received 80 Gy dosage
and adjuvant EBRT
Adjuvant/neoadjuvant
therapy, %
51
PSA, ng/mL
9.7±14.9
Comparators:
Gleason score, %:
2–6
7
8–10
68.3
59.5
4.8
Clinical stage, %:
T1
T2
T3
35.7
59.5
4.8
Retropubic RP
EBRT using 3D
conformal technique,
delivered in 1.8–2.0 Gy
daily fractions
(5 days/week) to a
prescribed dose of 55–
80 Gy
EBRT
RP
n
203
896
Response
rate, %
72.4
74.9
Age, years
70.9±7.2
63.5±7.8
Page 197 of 261
Time since primary
therapy, months
29
30
Adjuvant/neoadjuvant
therapy, %
33
28
PSA, ng/mL
9.1±12.7
7.3±7.2
Gleason score, %:
2–6
7
8–10
43.1
47.9
9.0
59.6
37.3
3.1
Clinical stage, %:
T1
35.8
62.2
FACT-P† component subscale scores were
reported for follow-up exceeding one year
* Expanded Prostate Index Composite
† Functional Assessment of Cancer Therapy
(prostate component)
Duration of
follow-up
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Outcomes assessed (relevant to this review)
Duration of
follow-up
N: 94 (33 LDRBT, 61 RP patients)
Intervention:
Safety
1 year
LDRBT eligibility:
125I
LDRBT with
intraoperatively
planned implant
technique, prescribed
to 145 Gy to cover the
prostate plus 3–5 mm
margin (except no
margin posteriorly)
Urinary Function
D1 and D30 to the
urethra were restricted
to 250 Gy and 220 Gy
respectively.
In addition, emotional functioning and global
HRQoL (both using EORTC QLQ-C30) were
assessed.
T2
T3
Page 198 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
57.1
7.1
37.4
0.4
Values are median±SD, except where
indicated.
‡ A control group used in the primary analysis
were not considered, given a secondary
analysis made direct comparison between
treatment modalities, in accordance with
inclusion criteria for this assessment.
(KirschnerHermanns et al
2008)
Level III-2
interventional
evidence
Single institution,
Germany
Downs and Black
quality score: 15/27
Accrual: January
1999 – December
2002
Overall quality
assessment: Poor
Prospective cohort
T1–T2a, PSA ≤ 10 ng/mL Gleason ≤ 6,
prostate volume < 60 mL and no substantial
residual urine
No eligibility for RP group was provided.
RP
Age, years†
64 (54–75)
PSA, ng/mL†
9.2 (1.6–55.6)
Gleason score†
5 (3–8)
Clinical stage, %:
T1
T2
T3
35
60
5
Dose to 10% of the
anterior rectal wall was
restricted to < 145 Gy.
OCO*
0.78 (0.08–2.67)
Max flow < 10 mL/s, %
30
Residual vol > 50 mL, %
34#
Post-operative
dosimetry was
performed at 30 days
following implant.
Max capacity < 200 mL, % 15
Comparator:
LDRBT
Age, years†
67 (57–75)
Perineal RP was
performed using the
extrasphincteric Young
Urinary symptoms at 1 year following treatment
Lower urinary tract symptoms (LUTS), urgency,
incontinence, stress incontinence, having to wear
pads and the bother associated with the above
symptoms
General HRQoL
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 199 of 261
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
Cost (1-year charge comparison)
NA
Comparator: RP
Hospital and outpatient records were used to
compare pre-operative, operative and postoperative charges for LDRBT and RP patients
based on diagnosis-related group indexed against
ICD-9 code.
N: 202
Intervention:
Safety
All patients were treated 1998–2002 with
either LDRBT or EBRT with T1 or T2 prostate
Two-stage (preoperative planning) 125I
LDRBT, prescribed to
Urinary, bowel and sexual function
PSA, ng/mL†
7.7 (3.2–17.0)
Gleason score†
5 (2–7)
approach, with wide
excision of the bladder
neck and
neurovascular bundles.
36
64
0
No patients received
adjuvant hormone
therapy.
Clinical stage, %:
T1
T2
T3
OCO*
0.74 (0.34–1.70)
Max flow < 10 mL/s, %
21
Residual vol > 50 mL, %
12#
Max capacity < 200 mL, % 6
† Median (range)
* Obstruction coefficient
# Chi square, p=0.019 (RP cf LDRBT)
(Kohan et al 2000)
Single centre, US
Accrual: June 1995
– September 1996
Level III-2
interventional
evidence
Prospective cohort
Downs and Black
quality score: 15/27
N: 60 consecutive men with clinically localised
prostate cancer (T1–T2, N0, M0) underwent
RP (38) and LDRBT with 125I (13) or 103Pd (9)
Age, years
Overall quality
assessment: Poor
PSA, ng/mL
Gleason
score
Single institution,
Canada
Level III-2
interventional
evidence
Downs and Black
LDRBT
61.2
(43–71)
71.1
(60–86)
18 (47.4)
20 (52.6)
7 (31.8)
15 (68.2)
8.4
34)
12 (2.2–
(2.3–37.7)
6 (4–8)
6 (4–8)
Clinical
stage, n (%):
T1
T2
(Tsui et al 2005)
RP
Retrospective
cohort
Data collected for brachytherapy patients and
Median
(range),
months
LDRBT:
Author & year,
location and
accrual period
Page 200 of 261
Accrual: 1998–
2000
Level of evidence
and quality
assessment
quality score: 15/27
Overall quality
assessment: Poor
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
cancer, PSA < 20.0 ng/mL and Gleason ≤ 8.
145 Gy (TG43)
radiotherapy patients differed
45 (18–63)
BT patients:
28 records had incomplete data and 10
records were unavailable at the time of the
study, leaving 76 EBRT and 86 LDRBT
patients for analysis.
All patients were
discharged without a
catheter and with an
alpha blocker for a
minimum of 3 months.
RT:
62 (18–79)
Age, years
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
LDRBT
RT
64.8±6.5
66.3±5.1
50 (63.3)
28 (35.4)
1 (1.3)
0 (0)
6.2±2.3
35 (47.9)
21 (28.8)
16 (21.9)
1 (1.4)
9.1±3.7
Stage, n (%)†:
T1c
T2a
T2b
T2c
PSA, ng/mL
Gleason score n (%)†:
≤6
7
8
83 (97.6)
2 (2.4)
0 (0)
30 (40.5)
41 (55.4)
3 (4.1)
Urinary symptoms, %:
Inc. frequency
Urgency
Weak stream
Nocturia
64.5
35
45.9
85.5
13.5†
9.6‡
26.9
46.2†
TURP, n (%)
3.5
9.2
α-blocker, %
3.5
6.6
Neoadjuvant
ADT,%
32.9
13.2*
Values are mean±SD unless otherwise
specified.
Fisher‘s exact is for categorical variables, two
sample t-test for normally distributed variables
Comparator:
18 MV photon 3D-CRT
prescribed to 75.6 Gy
in 1.8 Gy fractions
using a six-field
coplanar technique
Three gold seed
fiducials were inserted
before planning.
The prostate was
planned with a margin
of 7 mm posteriorly (at
the rectal interface)
and 10 mm elsewhere.
IPSS (self reported), clinician description of bowel
and sexual function, use of medications for
symptom management
3D-CRT patients:
RTOG late radiation morbidity scores, clinician
description of sexual function and use of
medications
Urinary, sexual and bowel symptoms were
reported at 6, 12, 18, 24, 30, 36 and 42 months
after (the beginning of) treatment.
The different scores are not comparable and have
not been presented.
Statistical comparisons were not possible and not
performed by the authors.
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention: LDRBT
with prescription dose
of 145 Gy using realtime planning; 0.3 cm3
of the rectal wall
received the target
dose of 145 Gy.
Safety
Mean,
months
and Wilcoxon rank sum tests for variables with
non-normal distributions.
Stage data were only available for 79 and 73
LDRBT and EBRT patients, respectively, while
Gleason scores were obtained only for 85 and
74 of these patients.
† p<0.001, * p=0.005, ‡ p=0.009
(Wyler et al 2009)
Single centre,
Switzerland
Accrual:
LDRBT patients,
March 2001 –
December 2004
EBRT patients,
January 2002 –
December 2004
Level III-2
interventional
evidence
Downs and Black
quality score: 14/27
Overall quality
assessment: Poor
Retrospective
cohort
N: 212 consecutive patients with clinically
localised prostate cancer
LDRBT
RP
n
70
142
Age, years
(range)
61
(49–75)
64
(47–75)
PSA, ng/mL
6.1
(1.1–12.8)
11.3
(0.3–24)
Gleason score
5.7 (4–7)
6.3 (5–9)
39
16
0
27
24
54
Clinical risk*, n:
Low
Intermediate
High
* Clinical risk was low (PSA < 10 ng/mL, stage
T1c–T2a and Gleason score < 7),
intermediate (PSA 10–20 ng/mL or stage T2b
or Gleason score = 7) or high (not defined).
Page 201 of 261
Only patients with prostate volume < 60 mL
and urinary flow rate > 10 mL/s were selected.
79% of LDRBT patients and 74% of RP
patients returned questionnaires.
Comparator: RP
(nerve sparing in select
cases of preoperatively potent
patients)
Urinary, bowel and sexual function
HRQoL questionnaires* assessed urinary and
bowel function, however, no analysable data
specific to urinary function were provided
* European Organization for Research and
Treatment Quality of Life Questionnaire (EORTCQLQ-C30), International Prostate Symptom Score
(IPSS) and International Index of Erectile Function
(IIEF-5)
General HRQoL
General QoL, including pain (not defined
specifically as urinary, bowel or sexual in origin)
was also measured using EORTC-QLQ surveys.
LDRBT: 28
RP: 20
Page 202 of 261
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
(Vicini et al 2002)
Level III-3
interventional
evidence
Comparison of two
matched single
arms
N: 6,877 men with prostate cancer, of whom
5,179 are not considered for this analysis*,
leaving data for 1,698 patients
Intervention: LDRBT;
radioactive source or
further treatment
details not specified
Effectiveness
Median, 36
months
Multicentre, US and
Germany
Accrual: 1989–
1998
Downs and Black
quality score: 12/27
Overall quality
assessment: Poor
LDRBT
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Centre 1)
(Centre 2)
n
207
330
Age, years
73
69
Follow-up,
months
62
78
PSA, ng/mL
6
6
Gleason
score
NR†
5
3D-EBRT
EBRT
(Centre 3)
(Centre 4)
n
357
313
Age, years
68
73
Follow-up,
months
46
51
PSA, ng/mL
6
6
Gleason
score
6
6
n
491
Age, years
61
Follow-up,
months
34
PSA, ng/mL
6
RP (Centre 5)
Gleason
Comparators: (3D)EBRT (dosed at a
range of 66–73 Gy)
and RP (treatment
details unspecified)
Five-year biochemical-free recurrence
Five-year overall survival
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
score
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Intervention:
Safety
Intra-operative 125I
LDRBT performed
under spinal or general
anaesthesia, with 57±9
sources implanted with
22±8 needles,
preferentially implanted
in the periphery (no
extra prostatic seeds
planned), prescribed to
145 Gy
Urinary, bowel and sexual function
Median,
months
Comparator:
Scores at times A, B and C, and the change in
score between times A and B, and times A and C
are compared for EBRT and LDRBT.
6
Loss to follow-up: None evident in any patient
group/centre.
Values are median, except where specified.
* These patients had one or more of the
following: PSA > 10 ng/L, Gleason score > 7,
clinical stage T3, an ineligible treatment (high
density radiotherapy, neutron therapy).
† Not reported. Reporting of Gleason score
was at the discretion of each participating
centre; although no median score is available,
this data was presented in a table for patients
with a score ≤ 6.
(Pinkawa et al
2009)
Single centre,
Germany
Accrual: 2003–
2006
Level III-3
interventional
evidence
Comparison of two
matched single
arms
Downs and Black
quality score: 16/27
LDRBT and EBRT
patients, matched
on age (±5 years,
prostate volume
±10 cc, use of
ADT and erectile
function (no ability
to have an
erection, poor
ability to have an
erection, erection
sufficient for sexual
intercourse)
Overall quality
assessment:
Moderate
N: 104 (52 in each group)
Age, years
Prostate
volume
LDRBT
EBRT
68 (51–77)
68 (48–77)
37 (18–60)
35 (22–68)
PSA, ng/mL
7
14)
8 (1.5–
(2.5–24)
Neo-ADT
14 (27)
14 (27)
Gleason
score < 7
50 (96)
39 (75)
T-stage ≤ 2a
51 (98)
43 (83)
Comorbidities
27 (52)
25 (48)
Comorbidities with incidence > 5%:
Page 203 of 261
Hypertension
CHD
Diabetes
COPD
11 (21)
6 (12)
6 (12)
4 (8)
11(21)
13 (25)
7 (14)
6 (12)
Values are median (range) or n (%).
3D conformal EBRT
patients were planned
and treated with a full
bladder with a fourfield technique using
15 MeV photons,
anterior/lateral margins
of 1.5 cm, and
Expanded Prostate Cancer Index Composite
(EPIC) questionnaire given to patients at or before
treatment (time A), 1 month after LDRBT or at the
last day of EBRT (time B) and a median time of
16 months following treatment (time C).
16
Specific outcomes are: urinary bother, bowel
bother, incontinence, pad usage, problem of
dripping urine or painful urination, bloody stools,
painful bowel movements, problem from increased
frequency of bowel movements, sexual function
score.
12–21
Range
BT: 12–24
EBRT:
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Page 204 of 261
LDRBT post implant dosimetry at 1 month,
(mean±SD)
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Ollendorf et al
2009a)
Health technology
assessment US
Patient accrual is
varied (HTA is
based on three
separate
systematic
reviews).
Included studies
were published
during January
1996 – May 2009
for RP and AS,
1995 – August
2008 for IMRT, and
1995 – August
2008 for LDRBT
(the LDRBT
systematic review
also updated the
IMRT review).
Level of evidence
for this HTA cannot
be assessed.
The systematic
reviews on which
the HTA is based
rely primarily on
non-comparative
evidence (level IV)
Quality: good
(Drummond &
Jefferson 1996)
Health technology
assessment (HTA)
D90, Gy
152±26
V100, %
91±6%
V150, %
65±13%
Urethra D30, Gy
207±30
Urethra D10, Gy
238±67
Rectum D2 cc, Gy
114±37
Rectum D0.1 cc, Gy
224±80
Adverse event rates
The HTA used adverse event rates from
systematic reviews, which required included
studies to contain ‗a preponderance‘ of
patients of clinical stage T1–T2a, Gleason
score ≤ 6 and PSA < 10 ng/mL.
However, studies including intermediate risk
patients were not excluded.
Baseline adverse event rates were taken from
Bacon et al (2003) and Andersson et al (2004)
Patient utilities
Stewart et al (2005) Dale et al (2008); Sullivan
& Ghushchyan (2006)
Transition probabilities
D‘Amico et al (1999); Alibhai et al (2003);
Horwitz et al (2005)
Costs
US Medicare and other sources
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Modelled economic analysis: cost–utility
N/A
craniocaudal and
dorsal margins of 1 cm
Treatment was
planned to 70.2–
72.0 Gy in 1.8–2.0 Gy
fractions.
Cost–utility analysis
comparing:
RP
EBRT (specifically
IMRT)
LDRBT
AS
Incremental cost, incremental QALY, incremental
cost-effectiveness ratio (cost per QALY)
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
Study population
(inclusion/exclusion criteria)
Intervention
Outcomes assessed (relevant to this review)
Duration of
follow-up
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Table notes:
3D-CRT = three-dimensional conformal radiotherapy (a type of EBRT); ADT = androgen deprivation therapy; AS = active surveillance; bNED = biochemical no evidence of disease (freedom from biochemical recurrence); LDRBT =
low-dose-rate brachytherapy; CT= computerised tomography; D90 = the dose delivered to 90% of the planned radiotherapy target; EBRT = external beam radiotherapy; EORTC = European Organisation for Research and Treatment
of Cancer; EORTC QLQ-C30 = EORTC quality of life questionnaire – cancer; EORTC QLQ-PR25 = EORTC quality of life questionnaire - prostate cancer module; EPIC = Expanded Prostate cancer Index Composite; FACT-P =
Functional Assessment of Cancer Therapy - Prostate module; HRQoL = health-related quality of life; HTA = health technology assessment; ICER = incremental cost effectiveness ratio; IIEF = International Index of Erectile Function;
IMRT = intensity modulated radiotherapy; IPSS = International Prostate Symptom Score; LHRHa = luteinising hormone releasing hormone analogue; PSA = prostate specific antigen; QALY = quality adjusted life year; RP = radical
prostatectomy; RTOG = Radiation Therapy Oncology Group; SF-36 = Short Form–36 health survey; UCLA-PCI = University of California, Los Angeles - Prostate Cancer Index; V100 = the volume of the planned radiotherapy target
that received 100% of the prescribed dose
Page 205 of 261
Study profiles of included case series
Page 206 of 261
Author & year,
location and
accrual period
Level of evidence
and quality
assessment
Study design
(Bucci et al 2002)
Case series
Case series
Single centre,
Canada
Level IV
interventional
evidence
Accrual: June 1998
– August 2000
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Single centre,
Canada
Level IV
interventional
evidence
Accrual: March
1999 – July 2005
Single centre, Israel
Level IV
interventional
evidence
Accrual: September
1996 – October
2001
Case series
PSA:
≤ 10 ng/mL
82%
10 - ≤ 15 ng/mL 18%
N: 484
Age, years
Mean 63.1 (SD±6.9)
Rate of urinary obstruction requiring catheterisation
Median =
12 months
125I
Increase obstructive or irritative symptoms (IPSS)
from baseline
Median =
41 months
LDRBT
D90 = 160.6 Gy
Rates of urinary urgency
Rates of urinary retention, urethral stricture and
catheterisation after 1 year following treatment
Gleason score
≤6
PSA
≤ 10 ng/mL
Case series
N: 400 consecutive patients with early stage
prostate cancer
Age, years
Median (range) = 65 (41–70)
NHMRC case series
quality score: 6/6
Clinical stage
T1c: 73%, >T2a: 27%
Overall quality
assessment: Good
Gleason score
98% of patients ≤ 7
Case series
LDRBT dosed to
144 Gy as per TG-43
protocol.
Clinical stage
T1c–T2a
PSA
91% of patients ≤ 10 ng/mL
(Keyes et al 2009)
Duration of
follow-up
Gleason score
≤ 7 (3+4 only)
Overall quality
assessment: Good
Case series
Outcomes assessed (relevant to this review)
Clinical stage
T1c-T2b
NHMRC case series
quality score: 6/6
(Sacco et al 2003)
N: 282
Age, years
Median 66 (38–78)
Overall quality
assessment: Good
Case series
Intervention
(Inclusion/exclusion criteria)
NHMRC case series
quality score: 6/6
(Crook et al 2008)
Study population
Case series
N: 712 eligible from 932 consecutive patients
LDRBT with a
prescribed dose of
either 145 Gy or
115 Gy, depending on
whether iodine or
palladium seeds were
used—324 (82%) and
73 (18%) of patients
respectively.
52 (13%) patients
received EBRT in
addition to LDRBT
125I LDRBT prescribed
Number of patients who developed acute urinary
retention requiring catheterisation
Median =
2.1 years
Median number of days to development of acute
urinary retention requiring catheterisation
Median (range) duration of catheterisation, days
Proportion of patients with acute urinary retention
among those who did and did not use
corticosteroids (dexamethasone)
Number of patients with gross haematuria
IPSS flare following treatment with LDRBT
Median =
Multicentre,
Canada.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Accrual: July 1998
– June 2003
Age
Median 65.5 (46–82) years
Level IV
interventional
evidence
Clinical stage
<T2c
NHMRC case series
quality score: 5/6
Gleason score
≤7
Overall quality
assessment: Good
PSA, ng/mL:
≤ 10
10 – ≤ 15
to a dose of 144 Gy
(TG-43) to cover
≥ 98% of the planning
target volume (1–5 mm
margins).
Late RTOG urinary and bowel toxicity
LDRBT using either
pre-planning or realtime techniques
Number of patients with urinary retention requiring
catheterisation
Erectile function
57.1
months
85.8%
14.2%
Follow-up at least 34 months:
144 excluded due to living in remote area, 35
less than 34 months follow-up, 41 with
insufficient data.
(Mabjeesh et al
2007)
Single centre, Israel
Accrual: June 1998
– June 2006
Case series
Case series
Level IV
interventional
evidence
N: 655 men with localised prostate cancer
Age, years
Mean±SD = 67.3±6.5
Clinical stage
T1–T2c
NHMRC case series
quality score: 5/6
Median time to onset of urinary retention requiring
catheterisation
Median duration of catheterisation
Gleason score
99.9% of patients ≤ 7
Overall quality
assessment: Good
Mean =
45 months
Number of patients with urethral stricture
PSA, ng/mL
Mean±SD = 7.75±3.45
Loss to follow-up:
None apparent.
(Matzkin et al 2003)
Case series
Single centre, Israel
Level IV
interventional
evidence
Accrual: not
reported
Case series
N:300
Group 1: 136 pre-planned
Group 2: 164 intraoperatively planned
Page 207 of 261
NHMRC case series
quality score: 5/6
Age, years:
G1: Mean 67.2
G2: Mean 68.4
Overall quality
assessment: Good
Clinical stage
≤ T2
Gleason score
≤6
PSA:
G1: Mean 8.69
125I
LDRBT
monotherapy
prescribed to a dose of
145 Gy if pre-planned,
or 160 Gy if planned
intraoperatively,
according to TG-43
recommendations.
Urinary symptoms and IPSS following implantation
Analyses
were limited
to
24 months
follow-up.
G2: Mean 7.95
Page 208 of 261
(Mitchell et al 2008)
Case series
Multicentre, UK
Level IV
interventional
evidence
Accrual: January
2003 – October
2006
Case series
N: 1,535 men treated with permanent seed
LDRBT
Age, median, years (range):
Centre 1: 63 (43–79)
Centre 2: 65 (40–79)
Centre 3: 63 (43–82)
NHMRC case series
quality score: 5/6
Overall quality
assessment: Good
LDRBT with pre-plan
D90 range of 179–
189 Gy
IPSS* at baseline, 6 weeks and 12 months
following implant
Median =
21 months
Median duration of catheterisation
Urethral stricture rates
*International Prostate Symptom Score
Clinical stage
T1c–T3a
Gleason score
> 97% of patients ≤ 7
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
PSA, ng/mL
≤7
(Stone et al 2010)
Case series
Single centre, US
Level IV
interventional
evidence
Accrual: 1990–
2006
Case series
Loss to follow-up:
NA, complete reporting for all patients
registered on database.
N: 395
Age, years
Mean 68.9 (SD±6.8)
Clinical stage
T1b–T3a
NHMRC case series
quality score: 5/6
Gleason score
≤7
98.2%
Overall quality
assessment: Good
PSA, ng/mL:
≤ 10
10 – ≤ 20
> 20
125I
(n=335) or 103Pd
(n=60) LDRBT
monotherapy. 52%
received androgen
deprivation therapy for
3 months before
implantation.
Rates of urinary retention
Note: may have overlapping population with Kao
2007.
Median = 6
years
125I
83.3%
14.4%
2.3%
LDRBT was
prescribed to a dose of
160 Gy (TG-43).
Prostate volume > 50 cc
85% of men treated with 125I LDRBT
(Zelefsky et al
2007a)
Single centre, US
Accrual: January
1998 – December
2004
Case series
Level IV
interventional
evidence
NHMRC case series
quality score: 5/6
Overall quality
Case series
N:562
Age
Not reported
Clinical stage
99.8% ≤ T2
Gleason score
99.8% ≤ 7
125I
LDRBT
monotherapy
prescribed to a dose of
144 Gy
Incidence of late Grade 2 and 3 NCI CTCAE rectal
and urinary side effects.
Median =
40 months
assessment: Good
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
(Kao et al 2008)
Case series
Single centre, US
Level IV
interventional
evidence
Accrual: June 1995
– February 2005
(MacDonald et al
2005)
PSA, ng/mL:
≤ 10
10 – ≤ 20
> 20
Case series
Single centre,
Canada
Level IV
interventional
evidence
Accrual: July 1998
– January 2002
NHMRC case series
quality score: 4/6
N: 643 men with localised prostate cancer
Age
Not reported
Clinical stage
T1a– T2c
NHMRC case series
quality score: 4/6
Overall quality
assessment:
Moderate
Case series
94.5%
5.3%
0.2%
LDRBT with D90 >
180 Gy, median =
197 Gy (range, 180–
267 Gy) via real-time
planning
Gleason score
98.8% of patients ≤ 7
Case series
Age
Median = 65 (49–80) years
Clinical stage
≤ T2
Gleason score
≤7
Overall quality
assessment:
Moderate
Acute urinary retention
Median =
4.5 years
Patient-reported urinary QoL (undefined scale)
Freedom from Grade 2 or higher rectal bleeding at
3 and 5 years (as per National Cancer Institute
Common Terminology Criteria for Adverse Events)
Physician-assessed erectile function (among
subjects potent before LDRBT procedure)
PSA
Median = 6.1 ng/mL
Loss to follow-up:
Urinary outcomes were available for 249
patients.
Erectile function data were available for 572
men, of whom 420 were potent and assessed
following treatment.
Patient numbers available for bowel outcomes
unclear.
N: 342 men potent at baseline
Change in median IPSS* from baseline
* International Prostate Symptom Score
125I
LDRBT
monotherapy
prescribed to a dose of
144 Gy to > 99% of the
planning target volume
(0.5–1.0 cm margin
superiorly and
inferiorly).
Physician and patient document rates of erectile
dysfunction at 1–3 years following implantation.
Follow-up
not reported
125I
Rates of urinary retention requiring catheterisation
Mean =
5 years
PSA
Mean = 6.7 (SD±3.3) ng/mL
Prostate volume < 50 cc
Page 209 of 261
(Eckman et al
2010)
Single centre, US
Accrual: 1995–
2007
Case series
Level IV
interventional
evidence
NHMRC case series
quality score: 3/6
Case series
N: 394
Age
Mean = 67.3 (SD±7.6) years
Clinical stage
99.5% < T3
Gleason score
LDRBT
monotherapy
prescribed to a dose of
145 Gy
Rates of urinary symptoms (frequency, hesitancy,
urgency, decreased force, haematuria, nocturia,
dysuria and use of medication for urinary
symptoms) among men without symptoms at
baseline
95.7% < 8
Overall quality
assessment:
Moderate
Page 210 of 261
Rates of bowel symptoms (diarrhoea, constipation,
rectal bleeding, pain with defecation and use of
medication for bowel symptoms) among men
without symptoms at baseline
PSA
Mean = 7.7 (SD±4.7) ng/mL
2.8% received adjuvant EBRT.
(Elshaikh et al
2003)
Single centre, US
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Accrual: 1996–
2001
Case series
Case series
Level IV
interventional
evidence
Age
Median = 69 years
Clinical stage
≤ T2
NHMRC case series
quality score: 3/6
Gleason score
Median 6 (4–8)
Overall quality
assessment:
Moderate
(Schafer et al 2008)
Case series
Single centre,
Germany
Level IV
interventional
evidence
Accrual: June 1998
– December 2003
N: 402
Rates of impaired potency, blood in the semen,
painful ejaculations and use of medication for
erectile dysfunction in men who did not report these
symptoms at baseline
125I
LDRBT
monotherapy
prescribed to a dose of
144 Gy according to
American
Brachytherapy Society
recommendations
Rates of intermittent self-catheterisation for urinary
retention following implantation
Follow-up
not
recorded
125I
Pad usage following implantation
Median =
51 months
PSA
Median = 6.45 ng/mL
Case series
N: 258 (296 treated consecutively, 38 patients
died before assessment)
Age
Median = 71 years
NHMRC case series
quality score: 2/6
Clinical stage
94% ≤ T2
Overall quality
assessment: Poor
Gleason score:
≤7
71%
≥8
0.4%
Unknown
28.6%
LDRBT
monotherapy
prescribed to a
minimum peripheral
dose > 140 Gy (TG43).
Faecal incontinence or bloody stools following
implantation
Questionnaires were sent out to all patients
simultaneously, at between 13 and 78 months
following implantation (median = 51 months).
PSA
Median = 7.3 ng/mL
Table notes:
LDRBT = low-dose-rate brachytherapy; IIEF = International Index of Erectile Function; IMRT = intensity modulated radiotherapy; IPSS = International Prostate Symptom Score; LHRHa = luteinising hormone releasing hormone
analogue; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PSA = prostate specific antigen; RTOG = Radiation Therapy Oncology Group
Appendix K
Other eligible case series
Acher, P.L., Popert, R. et al (2007). ‘Dynamic dose-feedback prostate brachytherapy in
patients with large prostates and/or planned transurethral surgery before implantation’,
BJU International, 99 (5), 1066–1071.
Albert, M., Song, J.S. et al (2008). ‘Defining the rectal dose constraint for permanent
radioactive seed implantation of the prostate’, Urologic Oncology: Seminars and Original
Investigations, 26 (2), 147–152.
Block, T., Czempiel, H. & Zimmermann, F. (2006). ‘Transperineal permanent seed
implantation of "low-risk" prostate cancer: 5-year-experiences in 118 patients’,
Strahlentherapie und Onkologie, 182 (11), 666–671.
Bottomley, D., Ash, D. et al (2007). ‘Side effects of permanent I125 prostate seed
implants in 667 patients treated in Leeds’, Radiotherapy and Oncology, 82 (1), 46–49.
Brown, D., Colonias, A. et al (2000). ‘Urinary morbidity with a modified peripheral
loading technique of transperineal 125I prostate implantation’, International Journal of
Radiation Oncology, Biology, Physics, 47 (2), 353–360.
Caffo, O., Fellin, G. et al (2006). ‘Prospective evaluation of quality of life after interstitial
brachytherapy for localized prostate cancer’, International Journal of Radiation Oncology,
Biology, Physics, 66 (1), 31–37.
Cesaretti, J.A., Kao, J. et al (2007). ‘Effect of low dose-rate prostate brachytherapy on the
sexual health of men with optimal sexual function before treatment: analysis at >= 7
years of follow-up’, BJU International, 100 (2), 362–367.
Ciezki, J.P., Klein, E.A. et al (2000). ‘Cost comparison of radical prostatectomy and
transperineal brachytherapy for localized prostate cancer’, Urology, 55 (1), 68–72.
D’Amico, A.V., Cormack, R. et al (2000). ‘Real-time magnetic resonance imaging-guided
brachytherapy in the treatment of selected patients with clinically localized prostate
cancer’, Journal of Endourology, 14 (4), 367–370.
Feigenberg, S.J., Lee, W.R. et al (2005). ‘Health-related quality of life in men receiving
prostate brachytherapy on RTOG 98-05’, International Journal of Radiation Oncology,
Biology, Physics, 62 (4), 956–964.
Ghaly, M., Wallner, K. et al (2003). ‘The effect of supplemental beam radiation on
prostate brachytherapy-related morbidity: morbidity outcomes from two prospective
randomized multicenter trials’, International Journal of Radiation Oncology, Biology,
Physics, 55 (5), 1288–1293.
Henderson, A., Ismail, A.K.A. et al (2004). ‘Toxicity and early biochemical outcomes
from (125)iodine prostate brachytherapy in the UK: a prospective study’, Clinical
Oncology, 16 (2), 95–104.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 211 of 261
Herstein, A., Wallner, K. et al (2005). ‘I-125 versus Pd-103 for low-risk prostate cancer:
Long-term morbidity outcomes from a prospective randomized multicenter controlled
trial’, Cancer Journal, 11 (5), 385–389.
Huyghe, E., Delannes, M. et al (2009). ‘Ejaculatory function after permanent I-125
prostate brachytherapy for localized prostate cancer’, International Journal of Radiation
Oncology, Biology, Physics, 74 (1), 126–132.
Ishiyama, H., Satoh, T. et al (2008). ‘Four-year experience of interstitial permanent
brachytherapy for Japanese men with localized prostate cancer’, Japanese Journal of
Clinical Oncology, 38 (7), 469–473.
Khaksar, S.J., Laing, R.W. et al (2006). ‘Biochemical (prostate-specific antigen) relapsefree survival and toxicity after I-125 low-dose-rate prostate brachytherapy’, BJU
International, 98 (6), 1210–1215.
Kiteley, R.A., Lee, W.R. et al (2002). ‘Radiation dose to the neurovascular bundles or
penile bulb does not predict erectile dysfunction after prostate brachytherapy’, 1 (2), 90–
94.
Kohan, A.D., Armenakas, N.A. & Fracchia, J.A. (2000). ‘The perioperative charge
equivalence of interstitial brachytherapy and radical prostatectomy with 1-year follow-up’,
Journal of Urology, 163 (2), 511–514.
Lawton, C.A., DeSilvio, M. et al (2007). ‘Results of a phase II trial of transrectal
ultrasound-guided permanent radioactive implantation of the prostate for definitive
management of localized adenocarcinoma of the prostate (Radiation Therapy Oncology
Group 98-05)’, International Journal of Radiation Oncology, Biology, Physics, 67 (1), 39–
47.
Lee, W.R., McQuellon, R.P. et al (2000). ‘A preliminary analysis of health-related quality
of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically
localized prostate cancer’, International Journal of Radiation Oncology, Biology, Physics,
46 (1), 77–81.
Lee, W.R., McQuellon, R.P. & McCullough, D.L. (2000). ‘A prospective analysis of
patient-reported quality of life after prostate brachytherapy’, Seminars in Urologic
Oncology, 18 (2), 147–151.
Mabjeesh, N., Chen, J. et al (2005). ‘Sexual function after permanent 125I-brachytherapy
for prostate cancer’, International Journal of Impotence Research, 17 (1), 96–101.
Mallick, S., Azzouzi, R. et al (2003). ‘Urinary morbidity after 125I brachytherapy of the
prostate’, BJU International, 92 (6), 555–558.
McElveen, T.L., Waterman, F.M. et al (2004). ‘Factors predicting for urinary incontinence
after prostate brachytherapy’, International Journal of Radiation Oncology, Biology,
Physics, 59 (5), 1395–1404.
Merrick, G.S., Butler, W.M. et al (2005). ‘The impact of radiation dose to the urethra on
brachytherapy-related dysuria’, Brachytherapy, 4 (1), 45–50.
Page 212 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Merrick, G.S., Butler, W.M. et al (2003). ‘Rectal function following brachytherapy with or
without supplemental external beam radiation: results of two prospective randomized
trials’, Brachytherapy, 2 (3), 147–157.
Merrick, G.S., Wallner, K. et al (2001). ‘Short-term sexual function after prostate
brachytherapy’, International Journal of Cancer, 96 (5), 313-319.
Meyer, J.P., Bell, C.R.W. et al (2008). ‘Brachytherapy for prostate cancer: is the
pretreatment prostate volume important?’, BJU International, 102 (11), 1585–1588.
Mierzwa, M.L., Barreft, W.L. et al (2008). ‘Randomized trial to assess the efficacy of
intraoperative steroid use in decreasing acute urinary retention after transperineal
radioactive iodine-125 implantation for prostate cancer’, Cancer, 113 (9), 2605–2609.
Morillo, V., Guinot, J.L. et al (2008). ‘Secondary effects and biochemical control in
patients with early prostate cancer treated with 125-I seeds’, Clinical and Translational
Oncology, 10 (6), 359–366.
Neill, M., Studer, G. et al (2007). ‘The nature and extent of urinary morbidity in relation
to prostate brachytherapy urethral dosimetry’, Brachytherapy, 6 (3), 173–179.
Niehaus, A., Merrick, G.S. et al (2006). ‘The influence of isotope and prostate volume on
urinary morbidity after prostate brachytherapy’, International Journal of Radiation
Oncology, Biology, Physics, 64 (1), 136–143.
Nobes, J.P., Khaksar, S.J. et al (2008). ‘Novel prostate brachytherapy technique:
Improved dosimetric and clinical outcome’, Radiotherapy and Oncology, 88 (1), 121–126.
Ohashi, T., Yorozu, A. et al (2005). ‘Acute urinary morbidity following I-125 prostate
brachytherapy’, International Journal of Clinical Oncology, 10 (4), 262–268.
Ohashi, T., Yorozu, A. et al (2006). ‘Serial changes of international prostate symptom
score following I-125 prostate brachytherapy’, International Journal of Clinical Oncology,
11 (4), 320–325.
Ohashi, T., Yorozu, A. et al (2007). ‘Rectal morbidity following I-125 prostate
brachytherapy in relation to dosimetry’, Japanese Journal of Clinical Oncology, 37 (2),
121–126.
Petit, J.H., Gluck, C. et al (2008). ‘Bicalutamide alone prior to brachytherapy achieves
cytoreduction that is similar to luteinizing hormone-releasing hormone analogues with
less patient-reported morbidity’, Urologic Oncology - Seminars and Original
Investigations, 26 (4), 372-377.
Petit, J.H., Gluck, C. et al (2007). ‘Androgen deprivation-mediated cytoreduction before
interstitial brachytherapy for prostate cancer does not abrogate the elevated risk of
urinary morbidity associated with larger initial prostate volume’, Brachytherapy, 6 (4),
267–271.
Pinkawa, M., Fischedick, K. et al (2006). ‘Health-related quality of life after permanent
interstitial brachytherapy for prostate cancer: correlation with postimplant CT scan
parameters’, Strahlentherapie und Onkologie, 182 (11), 660–665.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 213 of 261
Raben, A., Rusthoven, K.E. et al (2009). ‘Favorable toxicity and biochemical control
using real-time inverse optimization technique for prostate brachytherapy’,
Brachytherapy, 8 (3), 297–303.
Raina, R., Agarwal, A. et al (2003). ‘Long-term potency after iodine-125 radiotherapy for
prostate cancer and role of sildenafil citrate’, Urology, 62 (6), 1103–1108.
Roeloffzen, E.M.A., Lips, I.M. et al (2010). ‘Health-related quality of life up to six years
after 125I brachytherapy for early-stage prostate cancer’, International Journal of
Radiation Oncology, Biology, Physics, 76 (4), 1054–1060.
Saibishkumar, E P., Borg, J. et al (2008). ‘Loose seeds vs. stranded seeds: a comparison of
critical organ dosimetry and acute toxicity in 125I permanent implant for low-risk
prostate cancer’, Brachytherapy, 7 (2), 200–205.
Shah, J.N. & Ennis, R.D. (2006). ‘Rectal toxicity profile after transperineal interstitial
permanent prostate brachytherapy: use of a comprehensive toxicity scoring system and
identification of rectal dosimetric toxicity predictors’, International Journal of Radiation
Oncology, Biology, Physics, 64 (3), 817-824.
Solan, A.N., Cesaretti, J.A. et al (2009). ‘There is no correlation between erectile
dysfunction and dose to penile bulb and neurovascular bundles following real-time lowdose-rate prostate brachytherapy’, International Journal of Radiation Oncology, Biology,
Physics, 73 (5), 1468–1474.
Steggerda, M.J., Poel, H.G.V. & Moonen, L.M.F. (2008). ‘An analysis of the relation
between physical characteristics of prostate I-125 seed implants and lower urinary tract
symptoms: Bladder hotspot dose and prostate size are significant predictors’,
Radiotherapy and Oncology, 88 (1), 108–114.
Stone, N.N. & Stock, R.G. (2003). ‘Prospective assessment of patient-reported long-term
urinary morbidity and associated quality of life changes after 125I prostate
brachytherapy’, Brachytherapy, 2 (1), 32-39.
Thomas, C., Keyes, M. et al (2008). ‘Segmental urethral dosimetry and urinary toxicity in
patients with no urinary symptoms before permanent prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 72 (2), 447–455.
Thomas, M.D., Cormack, R. et al (2000). ‘Identifying the predictors of acute urinary
retention following magnetic-resonance-guided prostate brachytherapy’, International
Journal of Radiation Oncology, Biology, Physics, 47 (4), 905–908.
Vordermark, D., Noe, M. et al (2009). ‘Prospective evaluation of quality of life after
permanent prostate brachytherapy with I-125: importance of baseline symptoms and of
prostate-V150’, Radiotherapy and Oncology, 91 (2), 217–224.
Wallner, K., Merrick, G. et al (2002). ‘I-125 versus Pd-103 for low-risk prostate cancer:
morbidity outcomes from a prospective randomized multicenter trial’, Cancer Journal, 8
(1), 67–73.
Waterman, F.M. & Dicker, A.P. (2003). ‘Probability of late rectal morbidity in 125I
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
55 (2), 342–353.
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Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Williams, S.G., Millar, J.L. et al (2004). ‘Factors predicting for urinary morbidity following
(125)iodine transperineal prostate brachytherapy’, Radiotherapy and Oncology, 73 (1),
33–38.
Wust, P., von Borczyskowski, D.W. et al (2004). ‘Clinical and physical determinants for
toxicity of 125-I seed prostate brachytherapy’, Radiotherapy and Oncology, 73 (1), 39–48.
Zelefsky, M.J., Yamada, Y. et al (2007). ‘Five-year outcome of intraoperative conformal
permanent I-125 interstitial implantation for patients with clinically localized prostate
cancer’, International Journal of Radiation Oncology, Biology, Physics, 67 (1), 65–70.
Zelefsky, M.J., Yamada, Y. et al (2003). ‘Improved conformality and decreased toxicity
with intraoperative computer-optimized transperineal ultrasound-guided prostate
brachytherapy’, International Journal of Radiation Oncology, Biology, Physics, 55 (4),
956–963.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 215 of 261
Appendix L
Excluded studies
Incorrect population
Adeeb, N.E., Christodoulides, J.C. et al (2002). ‘CT guided pararectal seed implant for
localized prostate cancer: a preliminary report’, Journal of Medicine, 33 (1–4), 63–71.
Albert, M., Tempany, C.M. et al (2003). ‘Late genitourinary and gastrointestinal toxicity
after magnetic resonance image-guided prostate brachytherapy with or without
neoadjuvant external beam radiation therapy’, Cancer, 98 (5), 949–954.
Alexianu, M. & Weiss, G.H. (2000). ‘Radical prostatectomy versus brachytherapy for
early-stage prostate cancer’, Journal of Endourology, 14 (4), 325–328.
Anderson, J.F., Swanson, D.A. et al (2009). ‘Urinary side effects and complications after
permanent prostate brachytherapy: the MD Anderson Cancer Center Experience’,
Urology, 74 (3), 601-605.
Aoki, M., Miki, K. et al (2009). ‘Evaluation of rectal bleeding factors associated with
prostate brachytherapy’, Japanese Journal of Radiology, 27 (10), 444–449.
Ash, D., Bottomley, D. et al (2007). ‘A prospective analysis of tong-term quality of life
after permanent I-125 brachytherapy for localised prostate cancer’, Radiotherapy and
Oncology, 84 (2), 135-–139.
Bacon, C.G., Giovannucci, E. et al (2001). ‘The impact of cancer treatment on quality of
life outcomes for patients with localized prostate cancer’, Journal of Urology, 166 (5),
1804–1810.
Barker, J., Wallner, K. & Merrick, G. (2003). ‘Hematuria after prostate brachytherapy’,
Urology 61, 408–411.
Battermann, J.J. (2000). ‘I-125 implantation for localized prostate cancer: the Utrecht
University experience’, Radiotherapy and Oncology, 57 (3), 269–272.
Battermann, J.J., Boon, T.A. & Moerland, M.A. (2004). ‘Results of permanent prostate
brachytherapy, 13 years of experience at a single institution’, Radiotherapy and Oncology,
71 (1), 23–28.
Battermann, J.J. & Van Es, C.A. (2000). ‘The learning curve in prostate seed
implantation’, Cancer Radiotherapy 4 (suppl. 1), 119s–122s.
Beekman, M., Merrick, G.S. et al (2005). ‘Selecting patients with pretreatment postvoid
residual urine volume less than 100 mL may favorably influence brachytherapy-related
urinary morbidity’, Urology, 66 (6), 1266–1270.
Befort, C.A., Zelefsky, M.J. et al (2005). ‘A measure of health-related quality of life among
patients with localized prostate cancer: results from ongoing scale development’, Clinical
Prostate Cancer, 4 (2), 100–108.
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Bellizzi, K.M., Latini, D.M. et al (2008). ‘Fear of recurrence, symptom burden, and
health-related quality of life in men with prostate cancer’, Urology, 72 (6), 1269-1273.
Benoit, R.M., Naslund, M.J. & Cohen, J.K. (2000). ‘Complications after prostate
brachytherapy in the medicare population’, Urology, 55 (1), 91–96.
Beyer, D.C., Thomas, T. et al (2003). ‘Relative influence of Gleason score and
pretreatment PSA in predicting survival following brachytherapy for prostate cancer’,
Brachytherapy, 2 (2), 77–84.
Blaivas, J.G., Weiss, J.P. & Jones, M. (2006). ‘The pathophysiology of lower urinary tract
symptoms after brachytherapy for prostate cancer’, BJU International, 98 (6), 1233–1237.
Blank, L.E., Gonzalez Gonzalez, D. et al (2000). ‘Brachytherapy with transperineal (125)
Iodine seeds for localized prostate cancer’, Radiotherapy and Oncology, 57 (3), 307–313.
Blasko, J.C., Grimm, P.D. et al (2000). ‘The role of external beam radiotherapy with I125/Pd-103 brachytherapy for prostate carcinoma’, Radiotherapy and Oncology, 57 (3),
273–278.
Blatt, H.J., Abel, L.J. et al (2001). ‘Utilization of a self-administered questionnaire to
assess rectal function following prostate brachytherapy’, Urologic Nursing, 21 (5), 356–
359.
Brandeis, J., Pashos, C.L. et al (2000). ‘A nationwide charge comparison of the principal
treatments for early stage prostate carcinoma (brief record)’, Cancer, (8), 1792–1799.
Chen, A.B., D’Amico, A.V. et al (2006). ‘Patient and treatment factors associated with
complications after prostate brachytherapy’, Journal of Clinical Oncology, 24 (33), 5298–
5304.
Chen, R.C., Clark, J.A. et al (2008). ‘Treatment ‘mismatch’ in early prostate cancer: do
treatment choices take patient quality of life into account?’, Cancer, 112 (1), 61–68.
Clark, J.A., Inui, T.S. et al (2003). ‘Patients’ perceptions of quality of life after treatment
for early prostate cancer’, Journal of Clinical Oncology, 21 (20), 3777–3784.
Eapen, L., Kayser, C. et al (2004). ‘Correlating the degree of needle trauma during
prostate brachytherapy and the development of acute urinary toxicity’, International
Journal of Radiation Oncology, Biology, Physics, 59 (5), 1392–1394.
Ebara, S., Katayama, N. et al (2008). ‘Iodine-125 seed implantation (permanent
brachytherapy) for clinically localized prostate cancer. [Erratum appears in Acta Med
Okayama. 2008 Apr; 62(2):139 Note: Katayama, Yoshihisa [corrected to Katayama,
Norihisa]]’, Acta Medica Okayama, 62 (1), 9–13.
Elliott, S.P., Meng, M.V. et al (2007). ‘Incidence of urethral stricture after primary
treatment for prostate cancer: data from CaPSURE’, Journal of Urology, 178 (2), 529–
534.
Finney, G., Haynes, A.M. et al (2005). ‘Cross-sectional analysis of sexual function after
prostate brachytherapy’, Urology, 66 (2), 377–381.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 217 of 261
Gore, J.L., Kwan, L. et al (2009). ‘Survivorship beyond convalescence: 48-month qualityof-life outcomes after treatment for localized prostate cancer’, Journal of the National
Cancer Institute, 101 (12), 888–892.
Hashine, K., Kusuhara, Y. et al (2009). ‘Health-related quality of life using SF-8 and EPIC
Questionnaires after treatment with radical retropubic prostatectomy and permanent
prostate brachytherapy’, Japanese Journal of Clinical Oncology, 39 (8), 502–508.
Henderson, A., Cahill, D. et al (2002). ‘(125)Iodine prostate brachytherapy: outcome from
the first 100 consecutive patients and selection strategies incorporating urodynamics’,
BJU International, 90 (6), 567–572.
Henderson, A., Laing, R.W. & Langley, S.E.M. (2004). ‘Quality of life following treatment
for early prostate cancer: does low dose rate (LDR) brachytherapy offer a better
outcome? A review’, European Urology, 45 (2), 134–141.
Henkel, T.O. & Kahmann, F. (2000). ‘Permanent brachytherapy: prostate seed implants
as an out-patient treatment’, Archivio Italiano di Urologia, Andrologia, 72 (4), 295–301.
Hughes, S., Wallner, K. et al (2001). ‘Pre-existing histologic evidence of prostatitis is
unrelated to postimplant urinary morbidity’, International Journal of Cancer, 96, 79–82.
Ikeda, T. & Shinohara, K. (2009). ‘Peak flow rate is the best predictor of acute urinary
retention following prostate brachytherapy: Our experience and literature review’,
International Journal of Urology, 16 (6), 558-560.
Kakehi, Y., Takegami, M. et al (2007). ‘Health related quality of life in Japanese men with
localized prostate cancer treated with current multiple modalities assessed by a newly
developed Japanese version of the Expanded Prostate Cancer Index Composite’, Journal
of Urology, 177 (5), 1856–1861.
Kalakota, K., Rakhno, E. et al (2010). ‘Late rectal toxicity after prostate brachytherapy:
Influence of supplemental external beam radiation on dose-volume histogram analysis’,
Brachytherapy, 9 (2), 131–136.
Kobuke, M., Saika, T. et al (2009). ‘Prospective longitudinal comparative study of healthrelated quality of life in patients treated with radical prostatectomy or permanent
brachytherapy for prostate cancer’, Acta Medica Okayama, 63 (3), 129–135.
Koukourakis, G., Kelekis, N. et al (2009). ‘Brachytherapy for prostate cancer: a systematic
review’, Advances in Urology, article ID 327945.
Koutrouvelis, P.G., Gillenwater, J. et al (2003). ‘High and intermediate risk prostate cancer
treated with three-dimensional computed tomography-guided brachytherapy: 2–8- year
follow-up’, Radiotherapy and Oncology, 67 (3), 303–308.
Landis, D., Wallner, K. et al (2002). ‘Late urinary function after prostate brachytherapy’,
Brachytherapy, 1 (1), 21–26.
Larson, G., Pappas, N. & Hassoun, B. (2000). ‘Prostate cancer treatment with ultrasoundguided transperineal brachytherapy: analysis of the treatment results of our first 150
patients’, Journal of the Oklahoma State Medical Association, 93 (8), 391–396.
Page 218 of 261
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Liauw, S.L., Sylvester, J.E. et al (2006). ‘Second malignancies after prostate brachytherapy:
incidence of bladder and colorectal cancers in patients with 15 years of potential followup’, International Journal of Radiation Oncology, Biology, Physics, 66 (3), 669–673.
Martens, C., Pond, G. et al (2006). ‘Relationship of the International Prostate Symptom
score with urinary flow studies, and catheterization rates following 125I prostate
brachytherapy’, Brachytherapy, 5 (1), 9–13.
Martin, A.-G., Roy, J. et al (2007). ‘Permanent prostate implant using high activity seeds
and inverse planning with fast simulated annealing algorithm: a 12-year Canadian
experience’, International Journal of Radiation Oncology, Biology, Physics, 67 (2), 334–
341.
Merrick, G.S., Butler, W.M. et al (2002). ‘The dosimetry of prostate brachytherapyinduced urethral strictures’, International Journal of Radiation Oncology, Biology,
Physics, 52 (2), 461–468.
Mols, F., Stijns, P. et al (2009). ‘Health-related quality of life in I-125 prostate
brachytherapy patients treated with and without volume-reducing hormone therapy:
results of a short-term prospective study’, Journal of Endourology, 23 (1), 153–159.
Monahan, P.O., Champion, V. et al (2007). ‘What contributes more strongly to predicting
QOL during 1-year recovery from treatment for clinically localized prostate cancer: 4weeks-post-treatment depressive symptoms or type of treatment?’, Quality of Life
Research, 16 (3), 399–411.
Murakami, N., Itami, J. et al (2008). ‘Urethral dose and increment of international
prostate symptom score (IPSS) in transperineal permanent interstitial implant (TPI) of
prostate cancer’, Strahlentherapie und Onkologie, 184 (10), 515–519.
Namiki, S., Satoh, T. et al (2006). ‘Quality of life after brachytherapy or radical
prostatectomy for localized prostate cancer: a prospective longitudinal study’, Urology, 68
(6), 1230–1236.
Percarpio, B., Sanchez, P. et al (2000). ‘Prostate brachytherapy—the community hospital
experience’, Connecticut Medicine, 64 (9), 523–526.
Peschel, R.E., Colberg, J.W. et al (2004). ‘Iodine 125 versus palladium 103 implants for
prostate cancer: clinical outcomes and complications’, Cancer Journal, 10 (3), 170–174.
Pinkawa, M., Fischedick, K. et al (2006). ‘Association of neoadjuvant hormonal therapy
with adverse health-related quality of life after permanent iodine-125 brachytherapy for
localized prostate cancer’, Urology, 68 (1), 104–109.
Pinkawa, M., Piroth, M.D. et al (2010). ‘Rectal morbidity after permanent interstitial
brachytherapy for prostate cancer: impact of day 1 vs. day 30 computed tomographybased postimplant dosimetry’, Brachytherapy, 9 (1), 1–7.
Rempelakos, A., Katsilieris, J. et al (2005). ‘Prostate brachytherapy: A three-year
experience from the first 116 patients in Greece’, Journal of the Balkan Union of
Oncology, 10 (2), 219–222.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 219 of 261
Rubenstein, J.H., Katin, M.J. et al (2000). ‘Permanent urinary incontinence following
prostate brachytherapy is rare even in patients with prior transurethral resection’, Journal
of Brachytherapy International, 16 (1), 25–33.
Salem, N., Simonian-Sauve, M. et al (2003). ‘Predictive factors of acute urinary morbidity
after iodine-125 brachytherapy for localised prostate cancer: a phase 2 study’,
Radiotherapy and Oncology, 66 (2), 159–165.
Seo, P.H., D’Amico, A.V. et al (2004). ‘Assessing a prostate cancer brachytherapy
technique using early patient-reported symptoms: a potential early indicator for
technology assessment?’, Clinical Genitourinary Cancer, 3 (1), 38-–42.
Shah, S.A., Cima, R.R. et al (2004). ‘Rectal complications after prostate brachytherapy’,
Diseases of the Colon and Rectum, 47 (9), 1487–1492.
Shakespeare, D., Mitchell, D.M. et al (2007). ‘Recto-urethral fistula following
brachytherapy for localized prostate cancer’, Colorectal Disease, 9 (4), 328–331.
Shanahan, T.G., Mueller, P.W. et al (2004). ‘Image guided I125 prostate brachytherapy
with Hybrid Interactive Mick Technique in the community setting: how does it
compare?’, Technology in Research and Treatment, 3 (2), 209–215.
Shemtov, O.M., Radomski, S.B. & Crook, J. (2004). ‘Success of sildenafil for erectile
dysfunction in men treated with brachytherapy or external beam radiation for prostate
cancer’, Canadian Journal of Urology, 11 (6), 2450–2455.
Sherertz, T., Wallner, K. et al (2001). ‘Long-term urinary function after transperineal
brachytherapy for patients with large prostate glands’, International Journal of Radiation
Oncology, Biology, Physics, 51 (5), 1241–1245.
Snyder, K.M., Stock, R.G. et al (2001). ‘Defining the risk of developing grade 2 proctitis
following I-125 prostate brachytherapy using a rectal dose-volume histogram analysis’,
International Journal of Radiation Oncology, Biology, Physics, 50 (2), 335–341.
Stock, R.G., Kao, J. & Stone, N.N. (2001). ‘Penile erectile function after permanent
radioactive seed implantation for treatment of prostate cancer’, Journal of Urology, 165
(2), 436–439.
Stone, N.N., Ratnow, E.R. & Stock, R.G. (2000). ‘Prior transurethral resection does not
increase morbidity following real-time ultrasound-guided prostate seed implantation’,
Techniques in Urology, 6 (2), 123–127.
Stone, N.N. & Stock, R.G. (2007). ‘Long-term urinary, sexual, and rectal morbidity in
patients treated with iodine-125 prostate brachytherapy followed up for a minimum of 5
years’, Urology, 69 (2), 338–342.
Sugimoto, M., Takegami, M. et al (2008). ‘Health-related quality of life in Japanese men
with localized prostate cancer: Assessment with the SF-8’, International Journal of
Urology, 15 (6), 524–528.
Talcott, J.A., Clark, J.A. et al (2001). ‘Long-term treatment related complications of
brachytherapy for early prostate cancer: a survey of patients previously treated’, Journal of
Urology, 166 (2), 494–499.
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Teloken, P.E., Parker, M. et al (2009). ‘Predictors of response to sildenafil citrate
following radiation therapy for prostate cancer’, Journal of Sexual Medicine, 6 (4), 1135–
1140.
Tward, J.D., Lee, C.M. et al (2006). ‘Survival of men with clinically localized prostate
cancer treated with prostatectomy, brachytherapy, or no definitive treatment: impact of
age at diagnosis’, 107 (10), 2392–2400.
Van Gellekom, M.P.R., Moerland, M.A. et al (2005). ‘Quality of life of patients after
permanent prostate brachytherapy in relation to dosimetry’, International Journal of
Radiation Oncology, Biology, Physics, 63 (3), 772–780.
Ward-Smith, P., Wittkopp, D. & Sheldon, J.M. (2004). ‘Quality of life among men treated
with brachytherapy for prostate cancer’, Urologic Nursing, 24 (2), 95–99.
Wust, P., Postrach, J. et al (2008). ‘Postimplantation analysis enables improvement of
dose-volume histograms and reduction of toxicity for permanent seed implantation’,
International Journal of Radiation Oncology, Biology, Physics, 71 (1), 28–35.
Zelefsky, M.J., Hollister, T. et al (2000). ‘Five-year biochemical outcome and toxicity with
transperineal CT-planned permanent I-125 prostate implantation for patients with
localized prostate cancer’, International Journal of Radiation Oncology, Biology, Physics,
47 (5), 1261–1266.
Incorrect intervention
Abdel-Wahab, M., Reis, I.M. & Hamilton, K. (2008). ‘Second primary cancer after
radiotherapy for prostate cancer: A SEER analysis of brachytherapy versus external beam
radiotherapy’, International Journal of Radiation Oncology, Biology, Physics, 72 (1), 58–
68.
Alibhai, S.M. & Klotz, L.H. (2004). ‘A systematic review of randomized trials in localized
prostate cancer’, Canadian Journal of Urology, 11 (1), 2110–2117.
Bergman, J., Gore, J.L. et al (2009). ‘Erectile aid use by men treated for localized prostate
cancer’, Journal of Urology, 182 (2), 649–654.
Bergman, J., Kwan, L. & Litwin, M.S. (2010). ‘Improving decisions for men with prostate
cancer: translational outcomes research’, Journal of Urology, 183 (6), 2186–2191.
Bittner, N., Merrick, G.S. et al (2008). ‘Primary causes of death after permanent prostate
brachytherapy’, International Journal of Radiation Oncology, Biology, Physics, 72 (2),
433–440.
Brandeis, J.M., Litwin, M.S. et al (2000). ‘Quality of life outcomes after brachytherapy for
early stage prostate cancer’, Journal of Urology, 163 (3), 851–857.
Burnett, A.L., Aus, G. et al (2007). ‘Erectile function outcome reporting after clinically
localized prostate cancer treatment’, Journal of Urology, 178 (2), 597–601.
Chen, R.C., Clark, J.A. & Talcott, J.A. (2009). ‘Individualizing quality-of-life outcomes
reporting: how localized prostate cancer treatments affect patients with different levels of
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 221 of 261
baseline urinary, bowel, and sexual function’, Journal of Clinical Oncology, 27 (24), 3916–
3922.
Downs, T.M., Sadetsky, N. et al (2003). ‘Health-related quality of life patterns in patients
treated with interstitial prostate brachytherapy for localized prostate cancer: data from
CaPSURE’, Journal of Urology, 170 (5), 1822–1827.
Ellis, R.J., Sodee, D.B. et al (2000). ‘Feasibility and acute toxicities of radioimmunoguided
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
48 (3), 683–687.
Ellis, R.J., Zhou, H. et al (2007). ‘Rectal morbidity after permanent prostate
brachytherapy with dose escalation to biologic target volumes identified by SPECT/CT
fusion’, Brachytherapy, 6 (2), 149–156.
Eton, D.T., Lepore, S.J. & Helgeson, V.S. (2001). ‘Early quality of life in patients with
localized prostate carcinoma: an examination of treatment-related, demographic, and
psychosocial factors’, Cancer, 92 (6), 1451–1459.
Fijalkowski, M., Bialas, B. et al (2005). ‘Three-dimensional (3d) real-time conformal
brachytherapy - A novel solution for prostate cancer treatment: Part II. A feasibility
clinical pilot study’, Nowotwory J Oncol, 55 (2), 115-121.
Franca, C. A. d. S., Vieira, S. L. et al (2007). ‘The seven-year preliminary results of
Brachytherapy with Iodine-125 seeds for localized prostate cancer treated at a Brazilian
single-center’, International Brazilian Journal of Urology, 33 (6), 752–763.
Fulmer, B.R., Bissonette, E.A. et al (2001). ‘Prospective assessment of voiding and sexual
function after treatment for localized prostate carcinoma: comparison of radical
prostatectomy to hormonobrachytherapy with and without external beam radiotherapy’,
Cancer, 91 (11), 2046–2055.
Gelblum, D.Y. & Potters, L. (2000). ‘Rectal complications associated with transperineal
interstitial brachytherapy for prostate cancer’, International Journal of Radiation
Oncology, Biology, Physics, 48 (1), 119–124.
Gianino, M.M., Galzerano, M. et al (2009). ‘A comparative costs analysis of
brachytherapy and radical retropubic prostatectomy therapies for clinically localized
prostate cancer’, International Journal of Technology Assessment in Health Care, 25 (3),
411–414.
Gutman, S., Merrick, G.S. et al (2006). ‘Severity categories of the International Prostate
Symptom Score before, and urinary morbidity after, permanent prostate brachytherapy’,
BJU International, 97 (1), 62–68.
Han, B.H., Demel, K.C. et al (2001). ‘Patient reported complications after prostate
brachytherapy’, Journal of Urology, 166 (3), 953–957.
Ho, A. Y., Burri, R. J. et al (2009). ‘Radiation dose predicts for biochemical control in
intermediate-risk prostate cancer patients treated with low-dose-rate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 75 (1), 16–22.
Page 222 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Hoffelt, S.C., Wallner, K. & Merrick, G. (2004). ‘Epididymitis after prostate
brachytherapy’, Urology, 63 (2), 293–296.
Huang, G.J., Sadetsky, N. & Penson, D.F. (2010). ‘Health-related quality of life for men
treated for localized prostate cancer with long-term follow-up’, Journal of Urology, 183
(6), 2206–2212.
Jones, S., Wallner, K. et al (2002). ‘Clinical correlates of high intraprostatic brachytherapy
dose volumes’, International Journal of Radiation Oncology, Biology, Physics, 53 (2),
328–333.
Kang, S.K., Chou, R.H. et al (2001). ‘Acute urinary toxicity following transperineal
prostate brachytherapy using a modified Quimby loading method’, International Journal
of Radiation Oncology, Biology, Physics, 50 (4), 937–945.
Kang, S.K., Chou, R.H. et al (2002). ‘Gastrointestinal toxicity of transperineal interstitial
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
53 (1), 99–103.
Koutrouvelis, P., Hendricks, F. et al (2003). ‘Salvage reimplantation in patient with local
recurrent prostate carcinoma after brachytherapy with three dimensional computed
tomography-guided permanent pararectal implant’, Technology in Cancer Research &
Treatment, 2 (4), 339–344.
Koutrouvelis, P., Lailas, N. et al (2000). ‘Three-dimensional computed tomography. Guided brachytherapy for localized prostate cancer in patients with large volumes: fiveyear follow-up’, Journal of Brachytherapy International, 16 (1), 1-10.
Koutrouvelis, P., Lailas, N. et al (2000). ‘High- and low-risk prostate cancer treated with
3D CT-guided brachytherapy: 1- to 5-year follow-up’, Journal of Endourology, 14 (4),
357–366.
Koutrouvelis, P.G., Lailas, N. et al (2003). ‘Prostate cancer with large glands treated with
3-dimensional computerized tomography guided pararectal brachytherapy: up to 8 years
of follow-up’, Journal of Urology, 169 (4), 1331–1336.
Lee, H.K., Adams, M.T. et al (2010). ‘Seed implant retention score predicts the risk of
prolonged urinary retention after prostate brachytherapy’, International Journal of
Radiation Oncology, Biology, Physics, 76 (5), 1445–1449.
Lee, N., Wuu, C.S. et al (2000). ‘Factors predicting for postimplantation urinary retention
after permanent prostate brachytherapy’, International Journal of Radiation Oncology,
Biology, Physics, 48 (5), 1457–1460.
Lesperance, R.N., Kjorstadt, R.J. et al (2008). ‘Colorectal complications of external beam
radiation versus brachytherapy for prostate cancer’, American Journal of Surgery, 195 (5),
616–620.
Litwin, M.S., Gore, J.L. et al (2007). ‘Quality of life after surgery, external beam
irradiation, or brachytherapy for early-stage prostate cancer’, Cancer, 109 (11), 2239–
2247.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 223 of 261
Loblaw, D.A., Wallner, K. et al (2000). ‘Brachytherapy in patients with small prostate
glands’, Techniques in Urology, 6 (2), 64–69.
Locke, J., Ellis, W. et al (2002). ‘Risk factors for acute urinary retention requiring
temporary intermittent catheterization after prostate brachytherapy: a prospective study’,
International Journal of Radiation Oncology, Biology, Physics, 52 (3), 712–719.
Malcolm, J.B., Fabrizio, M.D. et al (2010). ‘Quality of life after open or robotic
prostatectomy, cryoablation or brachytherapy for localized prostate cancer’, Journal of
Urology, 183 (5), 1822–1828.
Mayadev, J., Merrick, G.S. et al (2010). ‘Permanent prostate brachytherapy in prostate
glands < 20 cm(3)’, International Journal of Radiation Oncology, Biology, Physics, 76 (5),
1450–1455.
Merrick, G.S., Butler, W.M. et al (2000). ‘Rectal function following prostate
brachytherapy’, International Journal of Radiation Oncology, Biology, Physics, 48 (3),
667–674.
Merrick, G.S., Butler, W.M. et al (2000). ‘Temporal resolution of urinary morbidity
following prostate brachytherapy’, International Journal of Radiation Oncology, Biology,
Physics, 47 (1), 121–128.
Merrick, G.S., Butler, W.M. et al (2002). ‘Permanent prostate brachytherapy-induced
morbidity in patients with grade II and III obesity’, Urology, 60 (1), 104–108.
Merrick, G.S., Butler, W.M. et al (2005). ‘Brachytherapy-related dysuria’, BJU
International, 95 (4), 597–602.
Merrick, G.S., Butler, W.M. et al (2004). ‘The impact of prostate volume and neoadjuvant
androgen-deprivation therapy on urinary function following prostate brachytherapy’,
Cancer Journal, 10 (3), 181–189.
Merrick, G.S., Butler, W.M. et al (2004). ‘Effect of transurethral resection on urinary
quality of life after permanent prostate brachytherapy’, International Journal of Radiation
Oncology, Biology, Physics, 58 (1), 81–88.
Merrick, G.S., Butler, W.M. et al (2007). ‘Long-term rectal function after permanent
prostate brachytherapy’, Cancer Journal, 13 (2), 95–104.
Merrick, G.S., Butler, W.M. et al (2006). ‘Risk factors for the development of prostate
brachytherapy related urethral strictures’, Journal of Urology, 175 (4), 1376–1380.
Merrick, G.S., Butler, W.M. et al (2005). ‘Erectile function after prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 62 (2), 437-447.
Merrick, G.S., Butler, W.M. et al (2003). ‘Long-term urinary quality of life after
permanent prostate brachytherapy’, International Journal of Radiation Oncology, Biology,
Physics, 56 (2), 454-461.
Merrick, G.S., Butler, W.M. et al (2003). ‘Dysuria after permanent prostate
brachytherapy’, International Journal of Radiation Oncology, Biology, Physics, 55 (4),
979-985.
Page 224 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Merrick, G.S., Butler, W.M. et al (2003). ‘Late rectal function after prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 57 (1), 4248.
Merrick, G.S., Butler, W.M. et al (2002). ‘Prophylactic versus therapeutic alpha-blockers
after permanent prostate brachytherapy’, Urology, 60 (4), 650-655.
Merrick, G.S., Butler, W.M. et al (2004). ‘The effect of hormonal manipulation on urinary
function following permanent prostate brachytherapy’, 3 (1), 22–29.
Merrick, G.S., Butler, W.M. et al (2004). ‘Influence of hormonal therapy on late rectal
function after permanent prostate brachytherapy with or without supplemental external
beam radiotherapy’, International Journal of Radiation Oncology, Biology, Physics, 58 (1),
68–74.
Merrick, G.S., Wallner, K.E. et al (2008). ‘Biochemical and functional outcomes following
brachytherapy with or without supplemental therapies in men (less-than or equal to) 50
years of age with clinically organ-confined prostate cancer’, American Journal of Clinical
Oncology: Clinical Trials, 31 (6), 539–544.
Monitto, D., Bozeman, G. et al (2003). ‘Spartanburg Regional Medical Center prostate
brachytherapy program: analysis of toxicity, implant quality and early efficacy’, Journal of
the South Carolina Medical Association, 99 (12), 365–371.
Moon, K., Stukenborg, G.J. et al (2006). ‘Cancer incidence after localized therapy for
prostate cancer’, Cancer, 107 (5), 991–998.
Moran, B.J., Stutz, M.A. & Gurel, M.H. (2004). ‘Prostate brachytherapy can be performed
in selected patients after transurethral resection of the prostate’, International Journal of
Radiation Oncology, Biology, Physics, 59 (2), 392–396.
Mueller, A., Wallner, K. et al (2004). ‘Perirectal seeds as a risk factor for prostate
brachytherapy-related rectal bleeding’, International Journal of Radiation Oncology,
Biology, Physics, 59 (4), 1047–1052.
Namiki, S., Kwan, L. et al (2009). ‘Distress and social dysfunction following prostate
cancer treatment: a longitudinal cross-cultural comparison of Japanese and American
men’, Prostate Cancer and Prostatic Diseases, 12 (1), 67–71.
Nguyen, P.L., D’Amico, A.V. et al (2007). ‘Patient selection, cancer control, and
complications after salvage local therapy for postradiation prostate-specific antigen
failure: a systematic review of the literature’, Cancer, 110 (7), 1417-1428.
Nieder, A.M., Porter, M.P. & Soloway, M.S. (2008). ‘Radiation therapy for prostate cancer
increases subsequent risk of bladder and rectal cancer: a population based cohort study’,
Journal of Urology, 180 (5), 2005–2009.
Ojha, R.P., Fischbach, L.A. et al (2010). ‘Acute myeloid leukemia incidence following
radiation therapy for localized or locally advanced prostate adenocarcinoma’, Cancer
Epidemiology, 34 (3), 274–278.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 225 of 261
Pieters, B.R., de Back, D.Z. et al (2009). ‘Comparison of three radiotherapy modalities on
biochemical control and overall survival for the treatment of prostate cancer: a systematic
review’, Radiotherapy and Oncology, 93 (2), 168–173.
Potters, L., Klein, E.A. et al (2004). ‘Monotherapy for stage T1-T2 prostate cancer: radical
prostatectomy, external beam radiotherapy, or permanent seed implantation’,
Radiotherapy and Oncology, 71 (1), 29–33.
Potters, L., Torre, T. et al (2001). ‘Potency after permanent prostate brachytherapy for
localized prostate cancer’, International Journal of Radiation Oncology, Biology, Physics,
50 (5), 1235–1242.
Prado, P.J., Juan, G. et al (2006). ‘Conformal prostate brachytherapy guided by realtime
dynamic dose calculations using permanent 125iodine implants: technical description and
preliminary experience’, Archivos Españoles de Urología, 59 (9), 933–940.
Sanchez-Ortiz, R.F., Broderick, G.A. et al (2000). ‘Erectile function and quality of life
after interstitial radiation therapy for prostate cancer’, International Journal of Impotence
Research, 12, S18–S24.
Sanda, M G., Dunn, R.L. et al (2008). ‘Quality of life and satisfaction with outcome
among prostate-cancer survivors’, New England Journal of Medicine, 358 (12), 1250–
1261.
Sarosdy, M.F. (2004). ‘Urinary and rectal complications of contemporary permanent
transperineal brachytherapy for prostate carcinoma with or without external beam
radiation therapy’, Cancer, 101 (4), 754–760.
Schiff, J.D., Bar-Chama, N. et al (2006). ‘Early use of a phosphodiesterase inhibitor after
brachytherapy restores and preserves erectile function’, BJU International, 98 (6), 1255–
1258.
Schover, L.R., Fouladi, R.T. et al (2002). ‘Defining sexual outcomes after treatment for
localized prostate carcinoma’, Cancer, 95 (8), 1773–1785.
Schwartz, D.J., Schild, S.E. et al (2005). ‘Factors associated with the frequency of selfintermittent catheterization after prostate brachytherapy’, International Journal of
Radiation Oncology, Biology, Physics, 61 (1), 60–63.
Sharkey, J., Cantor, A. et al (2002). ‘Brachytherapy versus radical prostatectomy in
patients with clinically localized prostate cancer’, Current Urology Reports, 3 (3), 250–
257.
Speight, J.L., Elkin, E.P. et al (2004). ‘Longitudinal assessment of changes in sexual
function and bother in patients treated with external beam radiotherapy or brachytherapy,
with and without neoadjuvant androgen ablation: data from CaPSURE’, International
Journal of Radiation Oncology, Biology, Physics, 60 (4), 1066–1075.
Stephenson, A.J., Scardino, P.T. et al (2004). ‘Morbidity and functional outcomes of
salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy’,
Journal of Urology, 172 (6), 2239–2243.
Page 226 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Taira, A.V., Merrick, G.S. et al (2009). ‘Erectile function durability following permanent
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
75 (3), 639–648.
Taira, A.V., Merrick, G.S. et al (2010). ‘Natural history of clinically staged low- and
intermediate-risk prostate cancer treated with monotherapeutic permanent interstitial
brachytherapy’, International Journal of Radiation Oncology, Biology, Physics, 76 (2),
349–354.
Theodorescu, D., Gillenwater, J.Y. & Koutrouvelis, P. G. (2000). ‘Prostatourethral-rectal
fistula after prostate brachytherapy: incidence and risk factors’, Cancer, 89 (10), 2085–
2091.
Tran, A., Wallner, K. et al (2005). ‘Rectal fistulas after prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 63 (1), 150–154.
Wehle, M.J., Lisson, S.W. et al (2004). ‘Prediction of genitourinary tract morbidity after
brachytherapy for prostate adenocarcinoma’, Mayo Clinic Proceedings, 79 (3), 314–317.
Wilt, T.J., MacDonald, R. et al (2008). ‘Systematic review: comparative effectiveness and
harms of treatments for clinically localized prostate cancer’, Annals of Internal Medicine,
148 (6), 435–448.
Woolsey, J., Bissonette, E. et al (2004). ‘Prospective outcomes associated with migration
from preoperative to intraoperative planned brachytherapy: a single center report’,
Journal of Urology, 172 (6 II), 2528–2531.
Wright, J.L., Newhouse, J.H. et al (2004). ‘Localization of neurovascular bundles on
pelvic CT and evaluation of radiation dose to structures putatively involved in erectile
dysfunction after prostate brachytherapy’, International Journal of Radiation Oncology,
Biology, Physics, 59 (2), 426–435.
Wu, A.K., Cooperberg, M.R. et al (2008). ‘Health-related quality of life in patients treated
with multimodal therapy for prostate cancer’, Journal of Urology, 180 (6), 2415–2422.
Zeliadt, S.B., Potosky, A.L. et al (2006). ‘Survival benefit associated with adjuvant
androgen deprivation therapy combined with radiotherapy for high- and low-risk patients
with non-metastatic prostate cancer’, International Journal of Radiation Oncology,
Biology, Physics, 66 (2), 395–402.
Incorrect comparator
Benoit, R.M., Naslund, M.J. & Cohen, J.K. (2000). ‘A comparison of complications
between ultrasound-guided prostate brachytherapy and open prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 47 (4), 909–913.
Gaudet, M., Vigneault, E. et al (2010). ‘Dose escalation to the dominant intraprostatic
lesion defined by sextant biopsy in a permanent prostate I-125 implant: a prospective
comparative toxicity analysis’, International Journal of Radiation Oncology, Biology,
Physics, 77 (1), 153–159.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 227 of 261
Grimm, P.D., Blasko, J.C. et al (2001). ‘10-year biochemical (prostate-specific antigen)
control of prostate cancer with I-125 brachytherapy’, International Journal of Radiation
Oncology, Biology, Physics, 51 (1), 31–40.
Henry, A.M., Al-Qaisieh, B. et al (2010). ‘Outcomes following iodine-125 monotherapy
for localized prostate cancer: the results of Leeds 10-year single-center brachytherapy
experience’, International Journal of Radiation Oncology, Biology, Physics, 76 (1), 50-56.
Joseph, J., Al-Qaisieh, B. et al (2005). ‘Prostate-specific antigen relapse-free survival in
patients with localized prostate cancer treated by brachytherapy’, Urologic Oncology:
Seminars and Original Investigations, 23 (4), 304.
Merrick, G.S., Butler, W.M. et al (2002). ‘The importance of radiation doses to the penile
bulb vs. crura in the development of postbrachytherapy erectile dysfunction’,
International Journal of Radiation Oncology, Biology, Physics, 54 (4), 1055–1062.
Raben, A., Sammons, S. et al (2007). ‘Initial comparison of inverse optimization, modified
peripheral technique, and geometric optimization as real-time intraoperative computer
planning options for permanent seed implantation of the prostate’, Brachytherapy, 6 (4),
238–245.
Stone, N.N., Potters, L. et al (2007). ‘Customized dose prescription for permanent
prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes’,
International Journal of Radiation Oncology, Biology, Physics, 69 (5), 1472–1477.
Incorrect outcome
Aaltomaa, S.H., Kataja, V.V. et al (2009). ‘Eight years experience of local prostate cancer
treatment with permanent I-125 seed brachytherapy: morbidity and outcome results’,
Radiotherapy and Oncology, 91 (2), 213–216.
Allen, Z.A., Merrick, G.S. et al (2005). ‘Detailed urethral dosimetry in the evaluation of
prostate brachytherapy-related urinary morbidity’, International Journal of Radiation
Oncology, Biology, Physics, 62 (4), 981–987.
Beyer, D.C. & Brachman, D.G. (2000). ‘Failure free survival following brachytherapy
alone for prostate cancer: comparison with external beam radiotherapy’, Radiotherapy
and Oncology, 57 (3), 263–267.
Bittner, N., Merrick, G.S. et al (2007). ‘The impact of acute urinary morbidity on late
urinary function after permanent prostate brachytherapy’, Brachytherapy, 6 (4), 258–266.
Cavanagh, W., Blasko, J.C. et al (2000). ‘Transient elevation of serum prostate-specific
antigen following 125I/103Pd brachytherapy for localized prostate cancer’, Seminars in
Urologic Oncology, 18 (2), 160–165.
Cesaretti, J.A., Stock, R.G. et al (2007). ‘A genetically determined dose-volume histogram
predicts for rectal bleeding among patients treated with prostate brachytherapy’,
International Journal of Radiation Oncology, Biology, Physics, 68 (5), 1410–1416.
Page 228 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Cesaretti, J.A., Stock, R.G. et al (2005). ‘ATM sequence variants are predictive of adverse
radiotherapy response among patients treated for prostate cancer’, International Journal
of Radiation Oncology, Biology, Physics, 61 (1), 196–202.
Cesaretti, J.A., Stone, N.N. & Stock, R.G. (2003). ‘Urinary symptom flare following I-125
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
56 (4), 1085–1092.
Chrouser, K.L., Leibovich, B.C. et al (2005). ‘Urinary fistulas following external radiation
or permanent brachytherapy for the treatment of prostate cancer’, Journal of Urology,
173 (6), 1953–1957.
Dosoretz, A.M., Chen, M.H. et al (2010). ‘Mortality in men with localized prostate cancer
treated with brachytherapy with or without neoadjuvant hormone therapy’, Cancer, 116
(4), 837–842.
Hollenbeck, B.K., Dunn, R.L. et al (2002). ‘Neoadjuvant hormonal therapy and older age
are associated with adverse sexual health-related quality-of-life outcome after prostate
brachytherapy’, Urology, 59 (4), 480–484.
Hurwitz, M.D., Cormack, R. et al (2000). ‘Three-dimensional real-time magnetic
resonance-guided interstitial prostate brachytherapy optimizes radiation dose distribution
resulting in a favorable acute side effect profile in patients with clinically localized prostate
cancer’, Techniques in Urology, 6 (2), 89–94.
Joseph, D.J., Woo, T.C.S. & Haworth, A. (2004). ‘Iodine-125 brachytherapy for prostate
cancer: first published Australian experience’, Australasian Radiology, 48 (2), 181–187.
Krupski, T., Bissonette, E.A. et al (2003). ‘The impact of prostate volume following
neoadjuvant androgen deprivation on quality of life and voiding symptoms in patients
undergoing permanent prostate brachytherapy’, European Urology, 43 (5), 467–472.
Landis, D.M., Schultz, D. et al (2005). ‘Acute urinary retention after magnetic resonance
image-guided prostate brachytherapy with and without neoadjuvant external beam
radiotherapy’, Urology, 65 (4), 750–754.
Lehrer, S., Cesaretti, J. et al (2006). ‘Urinary symptom flare after brachytherapy for
prostate cancer is associated with erectile dysfunction and more urinary symptoms before
implantation’, BJU International, 98 (5), 979–981.
Merrick, G.S., Butler, W.M. et al (2001). ‘Relationship between the transition zone index
of the prostate gland and urinary morbidity after brachytherapy’, Urology, 57 (3), 524–
529.
Merrick, G.S., Butler, W.M. et al (2002). ‘Erectile function after permanent prostate
brachytherapy’, International Journal of Oncology, Biology, Physics, 52 (4), 893–902.
Merrick, G.S., Wallner, K. et al (2001). ‘A comparison of radiation dose to the bulb of the
penis in men with and without prostate brachytherapy-induced erectile dysfunction’,
International Journal of Radiation Oncology, Biology, Physics, 50 (3), 597–604.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 229 of 261
Miller, D.C., Sanda, M.G. et al (2005). ‘Long-term outcomes among localized prostate
cancer survivors: Health-related quality-of-life changes after radical prostatectomy,
external radiation, and brachytherapy’, Journal of Clinical Oncology, 23 (12), 2772–2780.
Mishra, M.V., Shirazi, R. & Barrett, W.L. (2007). ‘Incidence and clinical course of
hemorrhagic radiation proctitis after iodine-125 prostate brachytherapy’, Clinical
genitourinary cancer, 5 (6), 397–400.
Ohashi, T., Yorozu, A. et al (2006). ‘Predictive factors of acute urinary retention requiring
catheterization following 125I prostate brachytherapy’, Japanese Journal of Clinical
Oncology, 36 (5), 285–289.
Ohebshalom, M., Parker, M. et al (2005). ‘The efficacy of sildenafil citrate following
radiation therapy for prostate cancer: temporal considerations’, Journal of Urology, 174
(1), 258–262.
Okaneya, T., Nishizawa, S. et al (2007). ‘Permanent prostate brachytherapy for Japanese
men: results from initial 100 patients with prostate cancer’, International Journal of
Urology, 14 (7), 602–606.
O’Reilly, P.H., Brooman, P.J.C. et al (2002). ‘A preliminary report on a patient-preference
study to compare treatment options in early prostate cancer’, BJU International, 90 (3),
253–256.
Patil, N., Crook, J. et al (2009). ‘The effect of obesity on rectal dosimetry after permanent
prostate brachytherapy’, Brachytherapy, 8 (2), 218–222.
Reis, F., Netto, N.R. Jr et al (2004). ‘The impact of prostatectomy and brachytherapy in
patients with localized prostate cancer’, International Urology and Nephrology, 36 (2),
187–190.
Smathers, S., Wallner, K. et al (2000). ‘Patient perception of local anesthesia for prostate
brachytherapy’, Seminars in Urologic Oncology, 18 (2), 142–146.
Steggerda, M.J., van der Poel, H.G. & Moonen, L.M.F. (2008). ‘Predicting urinary
morbidity after brachytherapy of localized prostate cancer’, European Urology
Supplements, 7 (12), 723–731.
Stock, R.G., Stone, N.N. et al (2002). ‘What is the optimal dose for 125I prostate
implants? A dose-response analysis of biochemical control, post-treatment prostate
biopsies, and long-term urinary symptoms’, Brachytherapy, 1 (2), 83–89.
Stone, N.N. & Stock, R G. (2005). ‘Reduction of pulmonary migration of permanent
interstitial sources in patients undergoing prostate brachytherapy’, Urology, 66 (1), 119–
123.
Talcott, J.A., Manola, J. et al (2003). ‘Time course and predictors of symptoms after
primary prostate cancer therapy’, Journal of Clinical Oncology, 21 (21), 3979–3986.
Tanaka, N., Fujimoto, K. et al (2009). ‘Variations in international prostate symptom
scores, uroflowmetric parameters, and prostate volume after I-125 permanent
brachytherapy for localized prostate cancer’, Urology, 74 (2), 407–411.
Page 230 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Teloken, P.E., Ohebshalom, M. et al (2007). ‘Analysis of the impact of androgen
deprivation therapy on sildenafil citrate response following radiation therapy for prostate
cancer’, Journal of Urology, 178 (6), 2521–2525.
Torres-Roca, J.F., Cantor, A.B. et al (2006). ‘Treatment of intermediate-risk prostate
cancer with brachytherapy without supplemental pelvic radiotherapy: a review of the H.
Lee Moffitt Cancer Center experience’, Urologic Oncology: Seminars and Original
Investigations, 24 (5), 384–390.
Tsai, H.K., D’Annico, A.V. et al (2007). ‘Androgen deprivation therapy for localized
prostate cancer and the risk of cardiovascular mortality’, Journal of the National Cancer
Institute, 99 (20), 1516–1524.
Wilt, T. (2003). ‘Prostate cancer (non-metastatic)’, Clinical Evidence, (10), 1023–1038.
Excluded for other reason (not in English, wrong type of article, or is a
review, systematic review or guideline that contains a majority of ineligible
articles and all eligible articles have already been included)
Aguilo Lucia, F., Suarez Novo, J.F. et al (2005). ‘Retrospective study of 130 patients with
organconfined prostate cancer treated with brachytherapy’, Actas Urologicas Españolas,
29 (1), 47–54.
Ash, D., Carey, B. et al (2005). ‘Long-term outcomes and morbidity after I125
brachytherapy for localised prostate cancer: an early UK series [1]’, Clinical Oncology, 17
(2), 127.
Bai, Q., Wang, Y. & Kaye, K.W. (2004). ‘Brachytherapy of 125I implantation for localized
prostate cancer (report of 41 cases)’, Zhonghua Nan Ke Xue (National Journal of
Andrology), 10 (5), 371–373.
Battermann, J.J., Jurgenliemk-Schulz, I.M. et al (2005). ‘Permanent prostate brachytherapy
treatment of a thousand patients in the UMC Utrecht’, Nederlands Tijdschrift voor
Urologie, 13 (3), 68–73.
Beerlage, H.P. (2003). ‘Alternative therapies for localized prostate cancer’, Current
Urology Reports, 4 (3), 216–220.
Beerlage, H.P., Thuroff, S. et al (2000). ‘Current status of minimally invasive treatment
options for localized prostate carcinoma’, European Urology, 37 (1), 2–13.
Bertetto, O., Bracarda, S. et al (2001). ‘Quality of life studies and genito-urinary tumors’,
Annals of Oncology, 12 (suppl. 3), S43–S48.
Bhatnagar, V., Stewart, S.T. et al (2006). ‘Estimating the risk of long-term erectile, urinary
and bowel symptoms resulting from prostate cancer treatment’, Prostate Cancer and
Prostatic Diseases, 9 (2), 136–146.
Borchers, H., Kirschner-Hermanns, R. et al (2004). ‘Permanent 125I-seed brachytherapy
or radical prostatectomy: a prospective comparison considering oncological and quality of
life results’, BJU International, 94 (6), 805–811.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 231 of 261
Brasacchio, R., Messing, E. et al (2001). Intraoperative treatment planning and guidance
for prostate brachytherapy: results of a prospective randomized study. International
Journal of Radiation Oncology, Biology, Physics, 51 (3) (suppl. 1), 200–201.
Budia Alba, A., Bosquet Sanz, M. et al (2007). ‘Indications, results and techniques of
permanent prostate brachitherapy for localized prostate cancer’, Actas Urologicas
Españolas, 31 (5), 452–468.
Cosset, J.M., Gomme, S. et al (2007). ‘Clinical and dosimetric analysis of 469 prostate
cancer patients treated in France in 2005 by permanent implant brachytherapy using the
Iodin 125 seeds IsoSeed Bebig: report to the French Economic Committee of Health
Products (CEPS)’, Cancer Radiothérapie, 11 (4), 206–213.
Crook, J., Lukka, H. et al (2001). ‘Systematic overview of the evidence for brachytherapy
in clinically localized prostate cancer’, Canadian Medical Association Journal, 164 (7),
975–981.
Dong, S.P., Jong, J.O. et al (2009). ‘Low-dose-rate brachytherapy for low- and
intermediate-risk groups of localized prostate cancer’, Korean Journal of Urology, 50 (7),
656–662.
Doust, J., Miller, E. et al (2004). ‘Clinical practice: review. A systematic review of
brachytherapy: is it an effective and safe treatment for localised prostate cancer?’,
Australian Family Physician, 33 (7), 525–529.
Doyen, J., Chamorey, E. et al (2009). ‘Iodine 125 prostate brachytherapy: prognostic
factors for long-term urinary, digestive and sexual toxicities’, Cancer Radiothérapie, 13
(8), 721–730.
Eastham, J.A. & Scardino, P.T. (2001). ‘Early diagnosis and treatment of prostate cancer’,
Disease-A-Month, 47 (9), 421–459.
Fernandez, P., De Paula, B. et al (2004). ‘Experience with external radiotherapy and HDR
and LDR permanent brachytherapy in the treatment of prostate cancer’, Oncologia, 27
(7), 9–12.
Forrer, P., Lummen, G. et al (2001). ‘Prostatic carcinoma’, Pharma-Kritik, 23 (15), 57–60.
Foster, W., Beaulieu, L. et al (2007). ‘The impact of 3D image guided prostate
brachytherapy on therapeutic ratio: the Quebec University Hospital experience’, Cancer
radiotherapy, 11 (8), 452–460.
Gardner, K.E. (2008). ‘Brachytherapy for prostate cancer’, Journal of the Arkansas
Medical Society, 105 (3), 69.
Garg, A.K., Mai, W.Y. et al (2006). ‘Radiation proctopathy in the treatment of prostate
cancer’, International Journal of Radiation Oncology, Biology, Physics, 66 (5), 1294–1305.
Glegg, M., Dodds, D. & Baxter, G.M. (2004). ‘Prostate brachytherapy: an option in the
treatment of early stage prostate cancer’, UroOncology, 4 (2), 53–69.
Glicksman, A.S. (2006). ‘Radiation management of prostate cancer’, Medicine and Health,
Rhode Island, 89 (2), 74–75.
Page 232 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Goldner, G., Ozdemiroglu, N. et al (2007). ‘Permanent interstitial brachytherapy (seeds)
for patients with primary localized prostate cancer: analysis of 100 patients’, Wiener
Klinische Wochenschrift, 119 (21–22), 647–653.
Gottfried, H.W., Schneider, E. & Messer, P.M. (2002). ‘Interstitial brachytherapy of
localized prostate carcinoma using permanently implanted radiation sources’, Urologe Ausgabe B, 42 (2), 142–151.
Grado, G.L. (2000). ‘Techniques to achieve optimal seed placement in salvage and
primary brachytherapy for prostate cancer’, Techniques in Urology, 6 (2), 157–165.
Hellawell, G.O., Ho, K. et al (2005). ‘Long-term outcomes and morbidity after I125
brachytherapy for localised prostate cancer: an early UK series [2]’, Clinical Oncology, 17
(1), 68–69.
Herkommer, K., Fuchs, T.A. et al (2005). ‘Radical prostatectomy for men aged < 56 years
with prostate cancer: cost of illness analysis’, Urologe, 44 (10), 1183–1188.
Hinnen, K.A., Battermann, J.J. et al (2010). ‘Long-term results for 921 patients treated
with I-125 permanent prostate brachytherapy’, Nederlands Tijdschrift voor Urologie, 18
(1), 31–36.
Hollenbeck, B.K. (2009). ‘Commentary on Provider case volume and outcomes following
prostate brachytherapy: Chen AB, D’Amico AV, Neville BA, Steyerberg EW, Earle CC,
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and
Women’s Hospital, Boston, MA’, Urologic Oncology: Seminars and Original
Investigations, 27 (5), 575.
Hummel, S., Paisley, S. et al (2003). Clinical and cost-effectiveness of new and emerging
technologies for early localised prostate cancer: a systematic review. Health Technology
Assessment, 7 (33), 1–170.
Huyghe, E., Bachaud, J.M. et al (2009). ‘Sexual dysfunction after curietherapy and
external radiotherapy of the prostate for localized prostate cancer’, Progres en Urologie,
19, S171–S174.
Incrocci, L., Slob, A.K. & Levendag, P.C. (2002). ‘Sexual (dys)function after radiotherapy
for prostate cancer: a review’, International Journal of Radiation Oncology, Biology,
Physics, 52 (3), 681–693.
Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (2007). Interstitial
brachytherapy in localised prostate cancer (Structured abstract) [Internet]. Institut fuer
Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Available from:
http://www.mrw.interscience.wiley.com/cochrane/clhta/articles/HTA32007000226/frame.html [Accessed 12/1/2011].
Irani, J. (2007). ‘Quality of life following radical prostatectomy and interstitial
radiotherapy’, Progres en Urologie, 17 (4), 863–863.
James, M. L. (2006). ‘Prostate cancer (early)’, Clinical Evidence (online).
Kahmann, F. (2001). ‘Iodine-125 implants against prostate cancer’, Arztliche Praxis
Urologie Nephrologie, (2), 26–27.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 233 of 261
Kanso, C., Etner, J. et al (2010). ‘Prostate cancer: medicoeconomic aspects’, Progres en
Urologie, 20 (2), 85–90.
Korb, L.J. & Brawer, M.K. (2001). ‘Modern brachytherapy for localized prostate cancers:
the northwest hospital (Seattle) experience’, Reviews in Urology, 3 (1), 51–62.
Lam Thomas, B. L., Simpson, M. et al (2008). 'Surgical management of localised prostate
cancer', Cochrane Database of Systematic Reviews, (2).
Mallick, S., Azzouzi, R. et al (2002). ‘Acute urinary complications after prostate iodine125 brachytherapy: evaluation and risk factors’, Journal de la Société Francaise de
Oncologique, 6 (2), 99–105.
Matzkin, H., Kaver, I. et al (2001). ‘I125 prostate brachytherapy: short-term results of the
first 150 patients in Israel’, Harefuah, 140 (8), 694–698, 807.
Merrick, G.S. & Butler, W.M. (2003). ‘The dosimetry of brachytherapy-induced erectile
dysfunction’, Medical Dosimetry, 28 (4), 271–274.
Merrick, G.S. & Butler, W.M. (2004). ‘Rectal function following permanent prostate
brachytherapy’, The West Virginia Medical Journal, 100 (1), 18–20.
Merrick, G.S., Butler, W.M. et al (2001). ‘Is brachytherapy comparable with radical
prostatectomy and external-beam radiation for clinically localized prostate cancer?’,
Techniques in Urology, 7 (1), 12–19.
Merrick, G.S., Wallner, K.E. & Butler, W.M. (2003). ‘Permanent interstitial brachytherapy
for the management of carcinoma of the prostate gland’, Journal of Urology, 169 (5),
1643–1652.
Nilsson, S., Norlen, B.J. & Widmark, A. (2004). ‘A systematic overview of radiation
therapy effects in prostate cancer’, Acta Oncologica, 43 (4), 316–381.
Norderhaug, I., Dahl, O. et al (2003). ‘Brachytherapy for prostate cancer: a systematic
review of clinical and cost effectiveness’, European Urology, 44 (1), 40–46.
Norderhaug, I., Johansen, T.B. et al (2002). ‘[Brachytherapy in prostatic cancer]’,
Tidsskrift for Den Norske Laegeforening, 122 (29), 2795–2798.
Ollendorf, D.A., Hayes, J. et al (2008). ‘Brachytherapy/proton beam therapy for clinically
localized, low-risk prostate cancer.’ Institute for Clinical and Economic Review (ICER),
p. 114.
Pommier, P., Delannes, M. et al (2006). ‘The French preliminary experience of the use of
a seed-projector for exclusive iodine 125 prostate brachytherapy: feasibility and acute
toxicity’, Cancer Radiothérapie, 10 (8), 559–564.
Prada, P.J., Hevia, M. et al (2005). ‘I125 low dose rate brachytherapy in localized prostate
cancer: preliminary results after 5 years’, Archivos Espa ñoles de Urología, 58 (3), 213–
226; discussion 224.
Page 234 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Robinson, J.W., Moritz, S. & Fung, T. (2002). ‘Meta-analysis of rates of erectile function
after treatment of localized prostate carcinoma’, International Journal of Radiation
Oncology, Biology, Physics, 54 (4), 1063–1068.
Smith, J.A. (2008). ‘Quality of life and satisfaction with outcome among prostate-cancer
survivors’, Urologic Oncology: Seminars and Original Investigations, 26 (6), 685.
Steggerda, M.J., Van Der Poel, H.G. & Moonen, L.M.F. (2006). ‘Is there any relation
between urinary morbidity and dose distribution after implantation of the prostate with I125 seeds?’, Nederlands Tijdschrift voor Urologie, 14 (5), 159–161.
Stokes, S.H. (2000). ‘Comparison of biochemical disease-free survival of patients with
localized carcinoma of the prostate undergoing radical prostatectomy, transperineal
ultrasound-guided radioactive seed implantation, or definitive external beam irradiation’,
International Journal of Radiation Oncology, Biology, Physics, 47 (1), 129–136.
Thompson, I., Thrasher, J.B. et al (2007). ‘Guideline for the management of clinically
localized prostate cancer: 2007 update’, Journal of Urology, 177 (6), 2106–2131.
Trojan, L., Harrer, K. et al (2007). ‘Complications and side effects of low dose rate
brachytherapy for the treatment of prostate cancer: data on a 13-year follow-up study
from Mannheim’, Urologe - Ausgabe A, 46 (11), 1542–1547.
Wallner, K. (2001). ‘Proctitis after prostate brachytherapy’, Journal of Brachytherapy
International, 17 (3), 211–216.
Wilt, T.J., Shamliyan, T. et al (2008). ‘Comparative effectiveness of therapies for clinically
localized prostate cancer.’ Agency for Healthcare Research and Quality, Review No. 13,
pp. 155.
Yorozu, A., Ohashi, T. et al (2006). ‘Erectile function one year after permanent I-125
seed implantation for prostate cancer’, Japanese Journal of Clinical Radiology, 51 (10),
1196–1201.
Yorozu, A., Toya, K. et al (2007). ‘Comparison between two 125I brachytherapy implant
techniques; preplanning and intraoperative method: dose escalation deteriorate acute
morbidity?’, Japanese Journal of Clinical Radiology, 52 (13), 1802–1806.
Zelefsky, M.J. (2006). ‘Psychological functioning associated with prostate cancer: crosssectional comparison of patients treated with radiotherapy, brachytherapy, or surgery.
Hervouet S, Savard J, Simard S, Ivers H, Laverdiere J, Vigneault E, Fradet Y, Lacombe L,
School of Psychology, Laval University, Quebec, Canada’, Urologic Oncology: Seminars
and Original Investigations, 24 (4 spec. issue), 377.
Zelefsky, M.J. (2006). ‘Quality of life of patients after permanent prostate brachytherapy
in relation to dosimetry. Van Gellekom MPR, Moerland MA, Van Vulpen M, Wijrdeman
HK, Battermann JJ, Department of Radiotherapy, University Medical Center Utrecht,
Utrecht, The Netherlands’, Urologic Oncology: Seminars and Original Investigations, 24
(4 spec. iss.), 377–378.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 235 of 261
Appendix M
Table 37
Unit costs for treating
localised prostate cancer
Unit costs of services and medications relating to low-dose-rate 125I brachytherapy for
localised prostate cancer over a 12-month period
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Initial urologist consult
SPECIALIST, REFERRED
CONSULTATION – SURGERY OR
HOSPITAL
$80.85
MBS item 104
Regardless of final
treatment decision,
men will be seen
initially by a urologist.
(Professional attendance at consulting
rooms or hospital by a specialist in the
practice of his or her specialty where
the patient is referred to him or her) –
INITIAL attendance in a single course
of treatment, not being a service to
which ophthalmology items 106, 109
or obstetric item 16401 apply
Initial radiation
oncologist consult
As above
$80.85
MBS item 104
Urine flow study
URINE FLOW STUDY including peak
urine flow measurement, not being a
service associated with a service to
which item 11919 applies
$26.05
MBS item
11900
Over a 20-month
period, almost as
many patients
receiving 15338 also
received a urine flow
study. It is likely that
this will be part of a
routine work-up for
patients receiving
brachytherapy.
Whole-body
radionuclide scan
BONE STUDY – whole body, with,
when undertaken, blood flow, blood
pool and delayed imaging on a
separate occasion (R)
$479.80
MBS item
61421
Over a 20-month
perioda, 62% of
patients who received
15338 also incurred a
WBBS item number—
either 61421 (76%) or
61425 (24%).
Computed
tomography scan
COMPUTED TOMOGRAPHY – scan of
upper abdomen and pelvis with
intravenous contrast medium and with
any scans of upper abdomen and
pelvis before intravenous contrast
injection, when undertaken, not for the
purposes of virtual colonoscopy, not
being a service to which item 56807 or
57007 applies (R) (K) (Anaes.)
$480.05
MBS item
56507
Over a 20-month
perioda, computerised
tomography is likely to
have been used on
close to 100% of men,
with 56507 and 56409
occurring equally as
often.
COMPUTED TOMOGRAPHY – scan
of pelvis only (iliac crest to pubic
symphysis) without intravenous
contrast medium not being a service
associated with a service to which
item 56401 applies (R) (K) (Anaes.)
$250.00
MBS item
56409
Mean cost of computed tomography
$365.03
(56507 +
56409) / 2
Page 236 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Component
Description
Cost (full
fee)
Source of
estimate
Pre-anaesthetic
consult
ANAESTHETIST, PREANAESTHESIA CONSULTATION
$40.60
MBS item
17610
Rationale and
assumptions
(Professional attendance by a medical
practitioner in the practice of
ANAESTHESIA)
– a BRIEF consultation involving a
targeted history and limited
examination (including the cardiorespiratory system)
– AND of not more than 15 minutes
duration, not being a service
associated with a service to which
items 2801–3000 apply
Brachytherapy
planning
BRACHYTHERAPY PLANNING,
computerised radiation dosimetry for
125I seed implantation of localised
prostate cancer, in association with
item 15338
$592.90
MBS item
15539
Brachytherapy implant
(urologist component)
PROSTATE, radioactive seed
$986.90
implantation of, urological component,
using transrectal ultrasound guidance,
for localised prostatic malignancy at
clinical stages T1 (clinically inapparent
tumour not palpable or visible by
imaging) or T2 (tumour confined within
prostate), with a Gleason score of less
than or equal to 7 and a prostate
specific antigen (PSA) of less than or
equal to 10 ng/mL at the time of
diagnosis. The procedure must be
performed by a urologist at an
approved site in association with a
radiation oncologist, and be
associated with a service to which
item 55603 applies.
MBS item
37220
Brachytherapy implant
(radiation oncologist
component)
PROSTATE, radioactive seed
implantation of, radiation oncology
component, using transrectal
ultrasound guidance, for localised
prostatic malignancy at clinical stages
T1 (clinically inapparent tumour not
palpable or visible by imaging) or T2
(tumour confined within prostate), with
a Gleason score of less than or equal
to 7 and a prostate specific antigen
(PSA) of less than or equal to
10 ng/mL at the time of diagnosis. The
procedure must be performed at an
approved site in association with a
urologist.
MBS item
15338
$884.25
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 237 of 261
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Transrectal ultrasound
PROSTATE, bladder base and
urethra, transrectal ultrasound scan
of, where performed:
$109.10
MBS item
55603
A transrectal
ultrasound is required
during the
brachytherapy
procedure to localise
seed placement.
INITIATION OF MANAGEMENT OF
ANAESTHESIA for brachytherapy
using radioactive sealed sources
$93.50
MBS item
21973
1:26 HOURS TO 1:30 HOURS
$112.20
MBS item
23063
Based on a procedure
time of between 76
and 90 minutes *Note:
item 23063 was not
identified as a fee
associated with
brachytherapy over a
20-month period.
FLUOROSCOPY using a mobile
image intensifier, in conjunction with a
surgical procedure lasting 1 hour or
more, not being a service associated
with a service to which another item in
this table applies (R)
$98.90
MBS item
60509
FLUOROSCOPY using a mobile
$63.75
image intensifier, in conjunction with a
surgical procedure lasting less than
1 hour, not being a service associated
with a service to which another item in
this table applies (R)
MBS item
60506
Mean cost of fluoroscopy (per patient
based on item usage in two-thirds of
cases)
(60509 +
60506) / 2 * 2/3
(a) personally by a medical
practitioner who undertook the
assessment referred to in (c) using a
transducer probe or probes that:
(i) have a nominal frequency of 7–
7.5 megahertz or a nominal
frequency range which includes
frequencies of 7–7.5 megahertz;
and
(ii) can obtain both axial and
sagittal scans in 2 planes at right
angles; and
(b) following a digital rectal
examination of the prostate by that
medical practitioner; and
(c) on a patient who has been
assessed by a specialist in urology,
radiation oncology or medical
oncology or a consultant physician in
medical oncology who has:
(i) examined the patient in the
60 days before the scan; and
(ii) recommended the scan for the
management of the patient‘s
current prostatic disease (R).
Anaesthesia
Intra-operative
imaging
Page 238 of 261
$54.21
Over a 20-month
period, these two
items combined were
present about twothirds of the time. This
procedure is likely
associated with intraoperative planning.
They were used
roughly equally as
often.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Post-implant
dosimetry
RADIATION SOURCE
LOCALISATION using a simulator or
x-ray machine or CT of a single area,
where views in more than 1 plane are
required, for brachytherapy planning
for 125I seed implantation of localised
prostate cancer, in association with
item 15338
$289.75
MBS item
15513
Hospital costs
AR-DRG L08B – Urethral proceduresCC (private)
$1,577.00
NHCDC Cost
Report Round
13
70% occur in private
and 30% occur in
public hospitals.
Private cost has been
adopted for public
hospitals, and wages
for radiation
oncologists, urologists
and anaesthetists are
assumed to be that of
the MBS fee.
125I
brachytherapy
seeds
Pre-loaded, stranded 125I seeds
$7,000.00
Prostheses List
code ON003
Listed benefit ranges
from $6,800 to $7,150,
depending upon
prescription; $,7000 is
taken as an
approximation.
Luteinising hormone
releasing hormone
analogue
GOSERELIN ACETATE
Subcutaneous implant (long acting)
10.8 mg (base) in pre-filled injection
syringe
$1,108.76
PBS code
8093Y
Assume usage in onethird of patients for
3 months prior.
Mean cost per patient for LHRHa
$369.59
8093Y * 1
courses / 3
(one-third of
patients)
a Data
from 1/9/2009 to 30/4/2010—the count of additional item numbers of men who received item 15338 in this period. The count will
underestimate the actual usage of services as patients may have accessed services before the period or may still access services after
the period that could reasonably be linked with the use of 15338. However, some services accessed over this time period will be
unrelated to 15338. Expert opinion from the Advisory Panel suggests that whole-body radionuclide scan and computerised tomography
scans are unnecessary in men with Gleason 6 (or less) disease and their use has only been costed for men with Gleason 7 prostate
cancer. However, it is clear that a proportion of men with Gleason 6 disease do receive these pre-treatment staging scans and the
overall estimation of cost associated with the treatment of Gleason 6 (or less) disease will therefore be underestimated.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 239 of 261
Table 38
Unit costs of services and medications relating to radical external beam radiotherapy for
localised prostate cancer over a 12-month period
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Initial urologist consult
As brachytherapy Table 37 above
$80.85
MBS item 104
Regardless of final
treatment decision,
men will be seen
initially by a urologist.
Initial Radiation
Oncologist consult
As brachytherapy Table 37 above
$80.85
MBS item 104
Whole-body
radionuclide scan
As brachytherapy Table 37 above
$479.80
MBS item
61421
Assume the use of
WBBS does not differ
between treatments
Computed
tomography scan
As brachytherapy Table 37 above
$365.03
(56507 +
56409) / 2
Assume the use of CT
does not differ
between treatments
Radiotherapy
simulation
SIMULATION FOR THREE
DIMENSIONAL CONFORMAL
RADIOTHERAPY without intravenous
contrast medium, where:
$622.45
MBS item
15550
CT Simulation without
contrast for 3D-CRT
$1059.25
MBS item
15562
2 phase 3D-CRT with
2 organs at risk and 2
planning volumes
Mean cost of computed tomography
(a) treatment set-up and technique
specifications are in preparations for
three-dimensional conformal
radiotherapy dose planning; and
(b) patient set-up and immobilisation
techniques are suitable for reliable CT
image volume data acquisition and
three dimensional conformal
radiotherapy treatment; and
(c) a high-quality CT-image volume
dataset must be acquired for the
relevant region of interest to be
planned and treated; and
(d) the image set must be suitable for
the generation of quality digitally
reconstructed radiographic images
Radiotherapy planning
DOSIMETRY FOR THREE
DIMENSIONAL CONFORMAL
RADIOTHERAPY OF LEVEL 3
COMPLEXITY - where:
(a)*
(b) dosimetry for a two-phase threedimensional conformal treatment plan
using CT image volume datasets with
at least one gross tumour volume, and
(i) two planning target volumes; or
(ii) two organ at risk dose goals or
constraints defined in the prescription.
or
(c)*
(d)*
* additional details can be accessed at
MBS online
Page 240 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Daily imaging /
verification
RADIATION ONCOLOGY
TREATMENT VERIFICATION multiple projection acquisition when
prescribed and reviewed by a radiation
oncologist and not associated with
item 15700 or 15710 - each
attendance at which treatment
involving three or more fields is
verified (ie maximum one per
attendance).
$2834.20
MBS item
15705
$76.60 per fraction at
37 fractions
Treatment Delivery
RADIATION ONCOLOGY
TREATMENT, using a dual photon
energy linear accelerator with a
minimum higher energy of at least
10MV photons, with electron facilities each attendance at which treatment is
given - 1 field - treatment delivered to
primary site (prostate)
$2086.80
MBS item
15248
$56.40 per fraction for
37 fractions (initial
field)
RADIATION ONCOLOGY
TREATMENT, using a dual photon
energy linear accelerator with a
minimum higher energy of at least
10MV photons, with electron facilities each attendance at which treatment is
given - 2 or more fields up to a
maximum of 5 additional fields
(rotational therapy being 3 fields) treatment delivered to primary site
(prostate)
$5305.80
MBS item
15263
Total cost of treatment delivery
$7392.60
15248 * 37
(fractions) +
15263 * 4
(fields) * 37
(fractions)
GOSERELIN ACETATE
Subcutaneous implant (long acting)
10.8 mg (base) in pre-filled injection
syringe
$1108.76
PBS code
8093Y
Mean cost per patient for LHRHa
$739.17
8093Y * 2
courses / 3 (a
third of
patients)
Luteinising hormone
releasing hormone
analogue (Gleason 7
patients only – Expert
opinion)a
$35.85 per fraction
per extra field for 37
fractions assuming a
5 field technique
Assume usage in 1/3
of Gleason 7 patients
for 3 months before
and 3 months after
implantation
Expert opinion from Advisory Panel members regard the use of LHRHa among men with Gleason 6 (or less) disease unnecessary. In
addition, the use of LHRHa is deemed far less likely among men with Gleason 3+4=7 disease than among the higher risk patients with
Gleason 4+3=7. Rather than create a separate subgroup for costing, LHRHa has been costed for all patients with Gleason 7 disease.
Therefore, the cost of treating men with Gleason 3+4=7 will be an over-estimate of the true costs.
a
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 241 of 261
Table 39
Unit costs of services and medications relating to radical prostatectomy for localised prostate
cancer over a 12-month period
Component
Description
Cost (full fee)
Source of
estimate
Rationale and
assumptions
Initial urologist
consult
As brachytherapy Table 37 above
$80.85
MBS item 104
Regardless of final
treatment decision, men
will be seen initially by a
urologist.
Whole-body
radionuclide scan
As brachytherapy Table 37 above
$479.80
MBS item
61421
Assume the use of
WBBS does not differ
between treatments.
Computed
tomography scan
As brachytherapy Table 37 above
$365.03
(56507 +
56409) / 2
Assume the use of CT
does not differ between
treatments.
Pre-anaesthetic
consult
As brachytherapy Table 37 above
$40.60
MBS item
17610
Surgeon fee
PROSTATECTOMY, radical,
involving total excision of the
prostate, sparing of nerves around
the bladder and bladder neck
reconstruction, not being a service
associated with a service to which
item 35551, 36502 or 37375
applies
$1,505.95
MBS item
37210
Assume nerve sparing,
assume no patient
undergoes
lymphadenectomy (low
risk?).
Assistant surgeon fee
Assistance at any operation
identified by the word ‗Assist.‘ for
which the fee exceeds $527.65 or
at a series of operations identified
by the word ‗Assist.‘ for which the
aggregate fee exceeds $527.65
$301.19
MBS item
51303
Assume assistant at all
procedures.
Hospital costs
AR-DRG M01Z – Major male pelvic
procedures (private)
$8,685
NHCDC Cost
Report Round
13 hospitals.
74% occur in private
and 26% occur in public
AR-DRG M01Z – Major male pelvic
procedures (public)
$13,874
INITIATION OF MANAGEMENT
OF ANAESTHESIA for radical
prostatectomy
$187.00
MBS item
20845
Based on a procedure
time of between 171
and 180 minutes.
2:51 HOURS TO 3:00 HOURS
$261.80
MBS item
23114
Examination of complexity level 7
biopsy material with multiple tissue
blocks, including specimen
dissection, all tissue processing,
staining, light microscopy and
professional opinion or opinions—1
or more separately identified
specimens
$470.00
MBS item
72838
Excised tissue is sent
for histopathological
review.
Packed red blood
cells
$32.90
(Medical
Services
Advisory
Committee
2006)
$329 per unit, assume
2 units in 5% of
patients.
Transfusion
$7.88
Anaesthesia
Pathology
Page 242 of 261
Mean cost of computed
tomography
$78.80 per transfusion,
assume 2 transfusions
in 5% of patients.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Component
Description
Cost (full fee)
Source of
estimate
Rationale and
assumptions
Cross-matching for
blood
Compatibility tests by crossmatch—all tests performed on any
one day for up to 6 units, including:
$109.65
MBS item
65099
Done on all patients
(a) all grouping checks of the
patient and donor; and
(b) examination for antibodies and,
if necessary, identification of any
antibodies detected; and
(c) (if performed) any tests
described in item 65060, 65070,
65090 or 65096
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 243 of 261
Table 40
Unit costs of services and medications relating to active surveillance for localised prostate
cancer over a 12-month period
Component
Description
Cost (full
fee)
Source of
estimate
Rationale and
assumptions
Initial urologist consult
As brachytherapy Table 37 above
$80.85
MBS item 104
Regardless of final
treatment decision,
men will be seen
initially by a urologist.
Initial radiation
oncologist consult
As brachytherapy Table 37 above
$80.85
MBS item 104
Prior to patient
deciding on active
surveillance, they may
wish to consult a
radiation oncologist
regarding
radiotherapy options
(LDRBT, EBRT)
Re-biopsy
PROSTATE, transrectal needle biopsy
of, using transrectal prostatic
ultrasound techniques and obtaining 1
or more prostatic specimens, being a
service associated with a service to
which item 55600 or 55603 applies
$265.40
MBS item
37219
Assume one biopsy
done within a year to
confirm
appropriateness for
active surveillance
PROSTATE, bladder base and
urethra, transrectal ultrasound scan of
$109.10
MBS item
55600
Examination of complexity level 4
biopsy material with 1 or more tissue
blocks, including specimen dissection,
all tissue processing, staining, light
microscopy and professional opinion
or opinions—12 to 17 separately
identified specimens
$210.35
MBS item
72827
Total cost for prostate biopsy in the
first 12 months
$584.85
37219 + 55600
+ 72827
PSA blood test
Prostate specific antigen – quantitation
in the monitoring of previously
diagnosed prostatic disease (including
a test described in item 66655)
$81.20
MBS item
66656 x 4 (per
year)
Patients will receive 4
PSA tests each year
for the duration of
active surveillance.
Follow-up consultation
by urologist
Each attendance SUBSEQUENT to
the first in a single course of
treatment
$162.40
MBS item 105
x 4 (per year)
Patients will visit a
urologist 4 times per
year for the duration
of active surveillance.
This likely represents
an overestimation, in
particular among men
who remain on active
surveillance for
several years.
Transrectal ultrasound
PROSTATE, bladder base and
urethra, transrectal ultrasound scan of
$109.10
MBS item
55600
From year 2 onwards,
patients will receive a
yearly transrectal
ultrasound. (In year 1
all patients are
assumed to receive a
repeat biopsy,
therefore an additional
TRUS is unlikely to be
required).
See Table 21 for a description of the management costs associated with active surveillance.
Page 244 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Glossary and abbreviations
3D-CRT
three-dimensional conformal radiotherapy (a type of EBRT)
ADT
androgen deprivation therapy
AHTA
Adelaide Health Technology Assessment
AIHW
Australian Institute of Health and Welfare
ANZAUS
Australian and New Zealand Association of Urological
Surgeons
AR-DRG
Australian Refined Diagnosis Related Groups
AS
active surveillance
ASTRO
American Society for Therapeutic Radiology and Oncology
AUA
American Urological Association
AUASI
American Urological Association Symptom Score
bNED
biochemical no evidence of disease (freedom from
biochemical recurrence)
BR
biochemical recurrence
BT
brachytherapy
CT
computerised tomography
CTC
Clinical Trials Centre
D90
the dose delivered to 90% of the planned radiotherapy target
EAU
European Association of Urology
EBRT
external beam radiotherapy
EORTC
European Organisation for Research and Treatment of
Cancer
EORTC QLQ-C30
EORTC quality of life questionnaire – cancer
EORTC QLQ-PR25
EORTC quality of life questionnaire – prostate cancer
module
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 245 of 261
EPIC
Expanded Prostate cancer Index Composite
FACT-P
Functional Assessment of Cancer Therapy – prostate module
Gleason grade
a measure of the aggressiveness of prostate cancer from 1
(well-differentiated, least aggressive) to 5 (undifferentiated,
most aggressive)
Gleason score
the sum of the two most common Gleason grades
HRQoL
health-related quality of life
HTA
health technology assessment
ICER
incremental cost-effectiveness ratio
IIEF
International Index of Erectile Function
IMRT
intensity modulated radiotherapy (a type of EBRT)
IPSS
International Prostate Symptom Score
LDR
low dose rate
LDRBT
low-dose-rate brachytherapy
LHRHa
luteinising hormone releasing hormone analogue
LUTS
lower urinary tract symptoms
MBS
Medicare Benefits Schedule
MRI
magnetic resonance imaging
MSAC
Medical Services Advisory Committee NCCN
National Comprehensive Cancer Network
NHMRC
National Health and Medical Research Council
NICE
National Institute for Health and Clinical Excellence
NSW
New South Wales
PBS
Pharmaceutical Benefits Scheme
PSA
prostate specific antigen
Page 246 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
PYLL
potential years of life lost
QALY
quality adjusted life year
RALP
robot-assisted laparoscopic prostatectomy
RCT
randomised controlled trial
RP
radical prostatectomy
RTOG
Radiation Therapy Oncology Group
SA
South Australian
SF-36
Short Form–36 health survey (a questionnaire of 36 questions
developed to measure HRQoL)
SPC
second primary cancer
TG-43
(or AAPM TG-43) American Association of Physicists in
Medicine Task Group 43—a report outlining a dosimetry
protocol to standardise the methods used to calculate dose to
patients receiving brachytherapy
TNM
Tumour–nodes–metastases
TRUS
transrectal ultrasound
TURP
transurethral resection of the prostate
UCLA-PCI
University of California, Los Angeles – Prostate Cancer Index
UICC
Union Internationale Contre le Cancer
USANZ
Urological Society of Australia and New Zealand
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 247 of 261
References
Abdel-Wahab, M., Reis, I.M. & Hamilton, K. (2008). ‘Second primary cancer after
radiotherapy for prostate cancer. A SEER analysis of brachytherapy versus external beam
radiotherapy’, International Journal of Radiation Oncology, Biology, Physics, 72 (1), 58–
68.
Abramowitz, M.C., Li, T. et al (2008). ‘The Phoenix definition of biochemical failure
predicts for overall survival in patients with prostate cancer’, Cancer, 112 (1), 55–60.
Acher, P., Popert, R. et al (2006). ‘Permanent prostate brachytherapy: dosimetric results
and analysis of a learning curve with a dynamic dose-feedback technique’, International
Journal of Radiation Oncology, Biology, Physics, 65 (3), 694–698.
Alibhai, S.M., Naglie, G. et al (2003). ‘Do older men benefit from curative therapy of
localized prostate cancer?’, Journal of Clinical Oncology, 21 (17), 3318–3327.
Al-Qaisieh, B., Carey, B. et al (2004). ‘The use of linked seeds eliminates lung
embolization following permanent seed implantation for prostate cancer’, International
Journal of Radiation Oncology, Biology, Physics, 59 (2), 397–399.
Al Otaibi, M., Ross, P. et al (2008). ‘Role of repeated biopsy of the prostate in predicting
disease progression in patients with prostate cancer on active surveillance’, Cancer, 113
(2), 286–292.
American Brachytherapy Society (2007). Prostate Low-Dose Rate Task Group [internet].
American Brachytherapy Society. Available from:
http://www.americanbrachytherapy.org/guidelines/index.cfm [accessed 25 September
2010].
American Urological Association (2007). Prostate cancer: guideline for the management
of clinically localized prostate cancer: 2007 update [internet]. Available from:
http://www.auanet.org/content/guidelines-and-quality-care/clinicalguidelines.cfm?sub=pc [accessed 29 March 2010].
Andersson, S.O., Rashidkhani, B. et al (2004). ‘Prevalence of lower urinary tract
symptoms in men aged 45-79 years: a population-based study of 40 000 Swedish men’,
BJU International, 94 (3), 327–331.
Andren, O., Fall, K. et al (2006). ‘How well does the Gleason score predict prostate
cancer death? A 20-year follow-up of a population based cohort in Sweden’, Journal of
Urology, 175 (4), 1337–1340.
Ankem, M.K., DeCarvalho, V.S. et al (2002). ‘Implications of radioactive seed migration
to the lungs after prostate brachytherapy’, Urology, 59 (4), 555–559.
Ash, D., Flynn, A. et al (2000). ‘ESTRO/EAU/EORTC recommendations on permanent
seed implantation for localized prostate cancer’, Radiotherapy and Oncology, 57 (3), 315–
321.
Page 248 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Aus, G., Damber, J.E. et al (2005). ‘Individualized screening interval for prostate cancer
based on prostate-specific antigen level: results of a prospective, randomized, populationbased study’, Archives of Internal Medicine, 165 (16), 1857–1861.
Australian Bureau of Statistics (ABS) (2008). 3302.0.55.001 - Life Tables, Australia, 20052007 [internet]. Australian Bureau of Statistics. Available from:
http://www.abs.gov.au/AUSSTATS/[email protected]/Lookup/3302.0.55.001Main+Features12
007-2009?OpenDocument [accessed 12 January 2011].
Australian Cancer Network Working Party (ed.) (2002). Clinical Practice Guidelines:
evidence-based information and recommendations for the management of localised
prostate cancer, National Health and Medical Research Council, Commonwealth of
Australia, Canberra, ACT.
Australian Government Department of Health and Ageing (2009a). Evaluation of the
National SMU Radiotherapy Trial [internet]. Australian Government. Available from:
http://www.health.gov.au/internet/main/publishing.nsf/Content/health-roi-singlemachine-unit-trial.htm [accessed 23 November 2010].
Australian Government Department of Health and Ageing (2009b). National Hospital
Cost Data Collection, Cost Report, Round 13 (2008–09). Commonwealth of Australia,
Canberra.
Australian Government Department of Health and Ageing (2010). Medicare Benefits
Schedule Book: operating from 1 May 2010. Commonwealth of Australia, Canberra.
Australian Institute of Health and Welfare (AIHW). (2008). Cancer Series no. 42. Cat. no.
CAN 38. AIHW, Canberra.
Australian Institute of Health and Welfare (AIHW) (2009a). ACIM (Australian Cancer
Incidence and Mortality) Books: Prostate cancer [internet]. AIHW. Available from:
http://www.aihw.gov.au/cancer/data/acim_books/index.cfm [accessed 23 November
2010].
Australian Institute of Health and Welfare (AIHW) (2009b). ACIM (Australian Cancer
Incidence and Mortality) Books: Breast cancer [internet]. AIHW. Available from:
http://www.aihw.gov.au/cancer/data/acim_books/index.cfm [accessed 23 November
2010].
Australian Institute of Health and Welfare (AIHW) (2009c). ACIM (Australian Cancer
Incidence and Mortality) Books: Colorectal cancer [internet]. AIHW. Available from:
http://www.aihw.gov.au/cancer/data/acim_books/index.cfm [accessed 23 November
2010].
Australian Institute of Health and Welfare (AIHW) (2009d). ACIM (Australian Cancer
Incidence and Mortality) Books: Lung, bronchus and trachea cancer [internet]. AIHW.
Available from: http://www.aihw.gov.au/cancer/data/acim_books/index.cfm [accessed
23 November 2010].
Australian Institute of Health and Welfare (AIHW) (2010). National Hospital Morbidity
Database: Procedures data cubes [internet]. AIHW. Available from:
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 249 of 261
http://www.aihw.gov.au/hospitals/datacubes/datacube_proc.cfm [accessed 30
November 2010].
Australian Institute of Health and Welfare (AIHW) & Australasian Association of Cancer
Registries (AACR) (2008). Cancer Series no. 46. Cat. no. CAN 42. AIHW, Canberra.
Bacon, C.G., Mittleman, M.A. et al (2003). ‘Sexual function in men older than 50 years of
age: results from the health professionals follow-up study’, Annals of Internal Medicine,
139 (3), 161–168.
Beckmann, K., Pinnock, C.B. et al (2009). ‘Clinical and socio-demographic profile of an
Australian multi-institutional prostate cancer cohort’, Asia Pacific Journal of Clinical
Oncology, 5 (4), 247–256.
Beyer, D.C. & Brachman, D.G. (2000). ‘Failure free survival following brachytherapy
alone for prostate cancer: comparison with external beam radiotherapy’, Radiotherapy
and Oncology, 57 (3), 263–267.
Bice, W.S. Jr., Prestidge, B.R. et al (1998). ‘Clinical impact of implementing the
recommendations of AAPM Task Group 43 on permanent prostate brachytherapy using
125I. American Association of Physicists in Medicine’, International Journal of Radiation
Oncology, Biology, Physics, 40 (5), 1237–1241.
Bill-Axelson, A., Holmberg, L. et al (2008). ‘Radical prostatectomy versus watchful
waiting in localized prostate cancer: the Scandinavian prostate cancer group-4
randomized trial’, Journal of the National Cancer Institute, 100 (16), 1144–1154.
Borchers, H., Kirschner-Hermanns, R. et al (2004). ‘Permanent 125I-seed brachytherapy
or radical prostatectomy: a prospective comparison considering oncological and quality of
life results’, BJU International, 94 (6), 805–811.
Bucci, J., Morris, W.J. et al (2002). ‘Predictive factors of urinary retention following
prostate brachytherapy’, International Journal of Radiation Oncology, Biology, Physics,
53 (1), 91–98.
Burdick, M.J., Reddy, C.A. et al (2009). ‘Comparison of biochemical relapse-free survival
between primary Gleason score 3 and primary Gleason score 4 for biopsy Gleason score
7 prostate cancer’, International Journal of Radiation Oncology, Biology, Physics, 73 (5),
1439–1445.
Buron, C., Le Vu, B. et al (2007). ‘Brachytherapy versus prostatectomy in localized
prostate cancer: Results of a French multicenter prospective medico-economic study’,
International Journal of Radiation Oncology, Biology, Physics, 67 (3), 812–822.
Capitanio, U., Karakiewicz, P.I. et al (2009). ‘The probability of Gleason score upgrading
between biopsy and radical prostatectomy can be accurately predicted’, International
Journal of Urology, 16 (5), 526–529.
Carlton, C.E. Jr., Dawoud, F. et al (1972). ‘Irradiation treatment of carcinoma of the
prostate: a preliminary report based on 8 years of experience’, Journal of Urology, 108 (6),
924-927.
Page 250 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Catalona, W.J. & Loeb, S. (2005). ‘The PSA era is not over for prostate cancer’, European
Urology, 48 (4), 541–545.
Cella, D., Hahn, E.A. & Dineen, K. (2002). ‘Meaningful change in cancer-specific quality
of life scores: differences between improvement and worsening’, Quality of Life
Research, 11 (3), 207–221.
Chan, T.Y., Partin, A.W. et al (2000). ‘Prognostic significance of Gleason score 3+4
versus Gleason score 4+3 tumor at radical prostatectomy’, Urology, 56 (5), 823–827.
Chen, R.C., Clark, J.A. & Talcott, J.A. (2009). ‘Individualizing quality-of-life outcomes
reporting: how localized prostate cancer treatments affect patients with different levels of
baseline urinary, bowel, and sexual function’, Journal of Clinical Oncology, 27 (24), 3916–
3922.
Chrouser, K.L., Leibovich, B.C. et al (2005). ‘Urinary fistulas following external radiation
or permanent brachytherapy for the treatment of prostate cancer’, Journal of Urology,
173 (6), 1953–1957.
Ciezki, J.P., Klein, E.A. et al (2000). ‘Cost comparison of radical prostatectomy and
transperineal brachytherapy for localized prostate cancer’, Urology, 55 (1), 68–72.
Collin, S.M., Martin, R.M. et al (2008). ‘Prostate-cancer mortality in the USA and UK in
1975-2004: an ecological study’, Lancet Oncology, 9 (5), 445-452.
Cooperberg, M.R., Lubeck, D.P. et al (2004). ‘The changing face of low-risk prostate
cancer: trends in clinical presentation and primary management’, Journal of Clinical
Oncology, 22 (11), 2141–2149.
Cooperberg, M.R., Pasta, D.J. et al (2005). ‘The University of California, San Francisco
Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative
predictor of disease recurrence after radical prostatectomy’, Journal of Urology, 173 (6),
1938–1942.
Coory, M.D. & Baade, P.D. (2005). ‘Urban-rural differences in prostate cancer mortality,
radical prostatectomy and prostate-specific antigen testing in Australia’, Medical Journal
of Australia, 182 (3), 112–115.
Crew, J.P., Jephcott, C.R. & Reynard, J.M. (2001). ‘Radiation-induced haemorrhagic
cystitis’, European Urology, 40 (2), 111–123.
Crook, J., Fleshner, N. et al (2008). ‘Long-term urinary sequelae following (125)iodine
prostate brachytherapy’, Journal of Urology, 179 (1), 141–145.
D’Amico, A.V., Chen, M.H. et al (2007). ‘Prostate cancer-specific mortality after radical
prostatectomy or external beam radiation therapy in men with 1 or more high-risk
factors’, Cancer, 110 (1), 56–61.
D’Amico, A.V., Manola, J. et al (2004). ‘6-month androgen suppression plus radiation
therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a
randomized controlled trial’, JAMA, 292 (7), 821–827.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 251 of 261
D’Amico, A.V., Whittington, R. et al (1998). ‘Biochemical outcome after radical
prostatectomy, external beam radiation therapy, or interstitial radiation therapy for
clinically localized prostate cancer’, JAMA, 280 (11), 969–974.
D’Amico, A.V., Whittington, R. et al (1999). ‘Pretreatment nomogram for prostatespecific antigen recurrence after radical prostatectomy or external-beam radiation therapy
for clinically localized prostate cancer’, Journal of Clinical Oncology, 17 (1), 168–172.
’‘’Dale, W., Basu, A. et al (2008). ‘Predicting utility ratings for joint health States from
single health States in prostate cancer: empirical testing of 3 alternative theories’, Medical
Decision Making, 28 (1), 102–112.
Dall’Era, M.A., Cooperberg, M.R. et al (2008). ‘Active surveillance for early-stage prostate
cancer: review of the current literature’, Cancer, 112 (8), 1650–1659.
Desch, C.E., Penberthy, L. et al (1996). ‘Factors that determine the treatment for local
and regional prostate cancer’, Medical Care, 34 (2), 152–162.
Downs, S.H. & Black, N. (1998). ‘The feasibility of creating a checklist for the assessment
of the methodological quality both of randomised and non-randomised studies of health
care interventions’, Journal of Epidemiology and Community Health, 52 (6), 377–384.
Draisma, G., Boer, R. et al (2003). ‘Lead times and overdetection due to prostate-specific
antigen screening: estimates from the European Randomized Study of Screening for
Prostate Cancer’, Journal of the National Cancer Institute, 95 (12), 868–878.
Drummond, M.F. & Jefferson, T.O. (1996). ‘Guidelines for authors and peer reviewers of
economic submissions to the BMJ. The BMJ Economic Evaluation Working Party’, BMJ,
313 (7052), 275–283.
Eade, T.N., Horwitz, E.M. et al (2008). ‘A comparison of acute and chronic toxicity for
men with low-risk prostate cancer treated with intensity-modulated radiation therapy or I125 permanent implant’, International Journal of Radiation Oncology, Biology, Physics,
71 (2), 338–345.
Eckman, M.H., Ying, J. et al (2010). ‘Longitudinal Analysis of Genitourinary and Bowel
Symptoms in Prostate Cancer Patients Following Brachytherapy’, American Journal of
Clinical Oncology – Cancer Clinical Trials, 33 (1), 1–10.
Eggener, S.E., Mueller, A. et al (2009). ‘A multi-institutional evaluation of active
surveillance for low risk prostate cancer’, Journal of Urology, 181 (4), 1635–1641;
discussion 1641.
Eggleston, J.C. & Walsh, P.C. (1985). ‘Radical prostatectomy with preservation of sexual
function: pathological findings in the first 100 cases’, Journal of Urology, 134 (6), 1146–
1148.
Elshaikh, M.A., Angermeier, K. et al (2003). ‘Effect of anatomic, procedural, and
dosimetric variables on urinary retention after permanent iodine-125 prostate
brachytherapy’, Urology, 61 (1), 152–155.
European Association of Urology (EAU) (2009). Guidelines on Prostate Cancer
[internet]. Available from:
Page 252 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/Prostate_Cancer.pdf
[accessed 29 March 2010].
Ferrer, M., Suarez, J.F. et al (2008). ‘Health-related quality of life 2 years after treatment
with radical prostatectomy, prostate brachytherapy, or external beam radiotherapy in
patients with clinically localized prostate cancer’, International Journal of Radiation
Oncology, Biology, Physics, 72 (2), 421–432.
Fowler, J.E. Jr., Barzell, W. et al (1979). ‘Complications of 125iodine implantation and
pelvic lymphadenectomy in the treatment of prostatic cancer’, Journal of Urology, 121
(4), 447–451.
Frank, S.J., Pisters, L.L. et al (2007). ‘An assessment of quality of life following radical
prostatectomy, high dose external beam radiation therapy and brachytherapy iodine
implantation as monotherapies for localized prostate cancer’, Journal of Urology, 177 (6),
2151–2156.
Gann, P.H., Hennekens, C.H. & Stampfer, M.J. (1995). ‘A prospective evaluation of
plasma prostate-specific antigen for detection of prostatic cancer’, JAMA, 273 (4), 289–
294.
Ganswindt, U., Paulsen, F. et al (2005). ‘70 Gy or more: which dose for which prostate
cancer?’, Journal of Cancer Research and Clinical Oncology, 131 (7), 407–419.
Giberti, C., Chiono, L. et al (2009). ‘Radical retropubic prostatectomy versus
brachytherapy for low-risk prostatic cancer: a prospective study’, World Journal of
Urology, 27 (5), 607–612.
Guedea, F., Ferrer, M. et al (2009). ‘Quality of life two years after radical prostatectomy,
prostate brachytherapy or external beam radiotherapy for clinically localised prostate
cancer: the Catalan Institute of Oncology/Bellvitge Hospital experience’, Clinical &
Translational Oncology, 11 (7), 470–478.
Hall, S.E., Holman, C.D. et al (2005). ‘Prostate cancer: socio-economic, geographical and
private-health insurance effects on care and survival’, BJU International, 95 (1), 51–58.
Hardie, C., Parker, C. et al (2005). ‘Early outcomes of active surveillance for localized
prostate cancer’, BJU International, 95 (7), 956–960.
Hashine, K., Kusuhara, Y. et al (2008). ‘A prospective longitudinal study comparing a
radical retropubic prostatectomy and permanent prostate brachytherapy regarding the
health-related quality of life for localized prostate cancer’, Japanese Journal of Clinical
Oncology, 38 (7), 480–485.
Horwitz, E.M., Thames, H.D. et al (2005). ‘Definitions of biochemical failure that best
predict clinical failure in patients with prostate cancer treated with external beam
radiation alone: a multi-institutional pooled analysis’, Journal of Urology, 173 (3), 797–
802.
Hummel, S., Paisley, S. et al (2003). ‘Clinical and cost-effectiveness of new and emerging
technologies for early localised prostate cancer: a systematic review’, Health Technology
Assessment, 7 (33), iii, ix-x, 1–157.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 253 of 261
Jao, S.W., Beart, R.W. Jr. et al (1987). ‘Colon and anorectal cancer after pelvic irradiation’,
Diseases of the Colon and Rectum, 30 (12), 953–958.
Jhaveri, F.M., Zippe, C.D. et al (1999). ‘Biochemical failure does not predict overall
survival after radical prostatectomy for localized prostate cancer: 10-year results’,
Urology, 54 (5), 884–890.
Johansson, J.E., Andren, O. et al (2004). ‘Natural history of early, localized prostate
cancer’, JAMA, 291 (22), 2713–2719.
Kang, D.E., Fitzsimons, N.J. et al (2007). ‘Risk stratification of men with Gleason score 7
to 10 tumors by primary and secondary Gleason score: results from the SEARCH
database’, Urology, 70 (2), 277–282.
Kao, J., Stone, N.N. et al (2008). ‘I-125 monotherapy using D90 implant doses of 180
GY or greater’, International Journal of Radiation Oncology, Biology, Physics, 70 (1), 96–
101.
Kattan, M.W., Eastham, J.A. et al (1998). ‘A preoperative nomogram for disease
recurrence following radical prostatectomy for prostate cancer’, Journal of the National
Cancer Institute, 90 (10), 766–771.
Keyes, M., Miller, S. et al (2009). ‘Urinary symptom flare in 712 I-125 prostate
brachytherapy patients: long-term follow-up’, International Journal of Radiation
Oncology, Biology, Physics, 75 (3), 649–655.
Keyes, M., Schellenberg, D. et al (2006). ‘Decline in urinary retention incidence in 805
patients after prostate brachytherapy: the effect of learning curve?’, International Journal
of Radiation Oncology, Biology, Physics, 64 (3), 825-834.
Khoddami, S.M., Shariat, S.F. et al (2004). ‘Predictive value of primary Gleason pattern 4
in patients with Gleason score 7 tumours treated with radical prostatectomy’, BJU
International, 94 (1), 42–46.
Kirschner-Hermanns, R., Brehmer, B. et al (2008). ‘Do patients with urodynamically
proven infravesical obstruction and detrusor overactivity have a higher risk for long-term
bothersome symptoms after brachytherapy in comparison to patients treated with radical
prostatectomy for localized prostate cancer?’, Current Urology, 2 (3), 135–141.
Klotz, L. (2005). ‘Active surveillance for prostate cancer: for whom?’, Journal of Clinical
Oncology, 23 (32), 8165–8169.
Klotz, L., Zhang, L. et al (2010). ‘Clinical results of long-term follow-up of a large, active
surveillance cohort with localized prostate cancer’, Journal of Clinical Oncology, 28 (1),
126–131.
Kohan, A.D., Armenakas, N.A. & Fracchia, J.A. (2000). ‘The perioperative charge
equivalence of interstitial brachytherapy and radical prostatectomy with 1-year follow-up’,
Journal of Urology, 163 (2), 511–514.
Krempien, R.C., Daeuber, S. et al (2003). ‘Image fusion of CT and MRI data enables
improved target volume definition in 3D-brachytherapy treatment planning’,
Brachytherapy, 2 (3), 164–171.
Page 254 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Kuban, D.A., Levy, L.B. et al (2006). ‘Comparison of biochemical failure definitions for
permanent prostate brachytherapy’, International Journal of Radiation Oncology, Biology,
Physics, 65 (5), 1487–1493.
Kuban, D.A., Thames, H.D. & Levy, L.B. (2004). ‘PSA after radiation for prostate
cancer’, Oncology (Williston Park), 18 (5), 595–604; discussion 605, 609.
Lau, W.K., Blute, M.L. et al (2001). ‘Prognostic factors for survival of patients with
pathological Gleason score 7 prostate cancer: differences in outcome between primary
Gleason grades 3 and 4’, Journal of Urology, 166 (5), 1692–1697.
Lee, W.R., deGuzman, A.F. et al (2000). ‘Postimplant analysis of transperineal interstitial
permanent prostate brachytherapy: evidence for a learning curve in the first year at a
single institution’, International Journal of Radiation Oncology, Biology, Physics, 46 (1),
83–88.
Lee, W.R., Hall, M.C. et al (2001). ‘A prospective quality-of-life study in men with
clinically localized prostate carcinoma treated with radical prostatectomy, external beam
radiotherapy, or interstitial brachytherapy’, International Journal of Radiation Oncology,
Biology, Physics, 51 (3), 614–623.
Lehnert, S., Reniers, B. & Verhaegen, F. (2005). ‘Relative biologic effectiveness in terms
of tumor response of 125I implants compared with 60Co gamma rays’, International
Journal of Radiation Oncology, Biology, Physics, 63 (1), 224–229.
Liberati, A., Altman, D.G. et al (2009). ‘The PRISMA statement for reporting systematic
reviews and meta-analyses of studies that evaluate health care interventions: explanation
and elaboration’, PLoS Med, 6 (7), e1000100.
Litwin, M.S., Sadetsky, N. et al (2004). ‘Bowel function and bother after treatment for
early stage prostate cancer: A longitudinal quality of life analysis from capsure’, Journal of
Urology, 172 (2), 515–519.
Liu, H.W., Malkoske, K. et al (2010). ‘The dosimetric quality of brachytherapy implants in
patients with small prostate volume depends on the experience of the brachytherapy team’,
Brachytherapy, 9 (3), 202–207.
Mabjeesh, N.J., Chen, J. et al (2007). ‘Preimplant predictive factors of urinary retention
after iodine 125 prostate brachytherapy’, Urology, 70 (3), 548–553.
MacDonald, A.G., Keyes, M. et al (2005). ‘Predictive factors for erectile dysfunction in
men with prostate cancer after brachytherapy: is dose to the penile bulb important?’,
International Journal of Radiation Oncology, Biology, Physics, 63 (1), 155–163.
Makarov, D.V., Sanderson, H. et al (2002). ‘Gleason score 7 prostate cancer on needle
biopsy: is the prognostic difference in Gleason scores 4 + 3 and 3 + 4 independent of the
number of involved cores?’, Journal of Urology, 167 (6), 2440–2442.
Matzkin, H., Kaver, I. et al (2003). ‘Iodine-125 brachytherapy for localized prostate
cancer and urinary morbidity: a prospective comparison of two seed implant methods Preplanning and intraoperative planning’, Urology, 62 (3), 497–502.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 255 of 261
McLeod, D.G. (2005). ‘The effective management of biochemical recurrence in patients
with prostate cancer’, Reviews in Urology, 7 suppl. 5, S29–36.
Medical Services Advisory Committee (MSAC) (2000). Brachytherapy for the treatment
of prostate cancer: MSAC application 1029, Commonwealth of Australia, Canberra.
Medical Services Advisory Committee (MSAC) (2005). Brachytherapy for the treatment
of prostate cancer: MSAC application 1089, Commonwealth of Australia, Canberra.
Medical Services Advisory Committee (MSAC) (2006). Laparoscopic remotely assisted
radical prostatectomy: MSAC application 1091, Commonwealth of Australia, Canberra.
Medicare Australia (2007). Medicare Benefits Schedule, July 2007 supplement [internet].
Department of Health and Ageing. Available from:
http://www.health.gov.au/internet/mbsonline/publishing.nsf/Content/MBSOnline2007 [accessed 23 February 2010].
Medicare Australia (2010). Medicare Item Reports: item number 15338 [internet].
Australian Government. Available from:
https://www.medicareaustralia.gov.au/statistics/mbs_item.shtml [accessed 25 September
2010].
Menon, M., Kaul, S. et al (2005). ‘Potency following robotic radical prostatectomy: a
questionnaire based analysis of outcomes after conventional nerve sparing and prostatic
fascia sparing techniques’, Journal of Urology, 174 (6), 2291–2296, discussion 2296.
Merlin, T., Weston, A. & Tooher, R. (2009). ‘Extending an evidence hierarchy to include
topics other than treatment: revising the Australian ‘levels of evidence’’, BMC Medical
Research Methodology, 9, 34.
Merrick, G.S., Galbreath, R.W. et al (2007). ‘Primary Gleason pattern does not impact
survival after permanent interstitial brachytherapy for Gleason score 7 prostate cancer’,
Cancer, 110 (2), 289–296.
Merrick, G.S., Wallner, K.E. & Butler, W.M. (2004). ‘Patient selection for prostate
brachytherapy: more myth than fact’, Oncology (Williston Park), 18 (4), 445–452;
discussion 452, 455–447.
Meuleman, E.J. & Mulders, P.F. (2003). ‘Erectile function after radical prostatectomy: a
review’, European Urology, 43 (2), 95–101; discussion 101–102.
Mitchell, D.M., Mandall, P. et al (2008). ‘Report on the early efficacy and tolerability of
I125 permanent prostate brachytherapy from a UK multi-institutional database’, Clinical
Oncology, 20 (10), 738–744.
Moon, K., Stukenborg, G.J. et al (2006). ‘Cancer incidence after localized therapy for
prostate cancer’, Cancer, 107 (5), 991-998.
Munro, N.P., Al-Qaisieh, B. et al (2010). ‘Outcomes from Gleason 7, intermediate risk,
localized prostate cancer treated with iodine-125 monotherapy over 10 years’,
Radiotherapy and Oncology, 96 (1), 34–37
Page 256 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Nag, S., Beyer, D. et al (1999). ‘American Brachytherapy Society (ABS) recommendations
for transperineal permanent brachytherapy of prostate cancer’, International Journal of
Radiation Oncology, Biology, Physics, 44 (4), 789-799.
National Comprehensive Cancer Network (NCCN) (2010). NCCN Clinical Practice
Guidelines in Oncology: prostate cancer [internet]. Available from:
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp [accessed 29 March
2010].
National Health and Medical Research Council (NHMRC) (2000). How to use the
evidence: assessment and application of scientific evidence. Biotext, Canberra.
National Health and Medical Research Council (NHMRC) (2009). NHMRC levels of
evidence and grades for recommendations for developers of guidelines [internet].
NHMRC, Commonwealth of Australia. Available from:
http://www.nhmrc.gov.au/guidelines/developers.htm [accessed 25 September 2010].
National Institute for Health and Clinical Excellence (NICE) (2008). Prostate cancer:
diagnosis and treatment [internet]. NICE. Available from: www.nice.org.uk/CG058
[accessed 29 March 2010].
Nieder, A.M., Porter, M.P. & Soloway, M.S. (2008). ‘Radiation therapy for prostate cancer
increases subsequent risk of bladder and rectal cancer: a population-based cohort study’,
Journal of Urology, 180 (5), 2005–2009.
Nielsen, M.E., Makarov, D.V. et al (2008). ‘Is it possible to compare PSA recurrence-free
survival after surgery and radiotherapy using revised ASTRO criterion –’nadir + 2’?’,
Urology, 72 (2), 389–393; discussion 394–385.
Ollendorf, D.A., Hayes, J. et al (2008). Brachytherapy/proton beam therapy for clinically
localized, low-risk prostate cancer. Institute for Clinical and Economic Review (ICER),
Boston, MA.
Ollendorf, D.A., Hayes, J. et al (2009a). Management options for low-risk prostate cancer:
a report on comparative effectiveness and value Institute for Clinical and Economic
Review (ICER), Boston, MA.
Ollendorf, D.A., Hayes, J. et al (2009b). Active surveillance & radical prostatectomy for
the management of clinically-localized, low risk prostate cancer. Institute for Clinical and
Economic Review (ICER), Boston, MA.
Osoba, D., Bezjak, A. et al (2005). ‘Analysis and interpretation of health-related qualityof-life data from clinical trials: basic approach of the National Cancer Institute of Canada
Clinical Trials Group’, European Journal of Cancer, 41 (2), 280–287.
Partin, A.W., Mangold, L.A. et al (2001). ‘Contemporary update of prostate cancer staging
nomograms (Partin Tables) for the new millennium’, Urology, 58 (6), 843-848.
Patel, V.R., Tully, A.S. et al (2005). ‘Robotic radical prostatectomy in the community
setting-—the learning curve and beyond: initial 200 cases’, Journal of Urology, 174 (1),
269–272.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 257 of 261
Pearson, S.D., Ladapo, J. & Prosser, L. (2007). Intensity modulated radiation therapy for
localized prostate cancer. Institute for Clinical and Economic Review (ICER), Boston,
MA.
Pickles, T., Keyes, M. et al (2010). ‘Brachytherapy or conformal external radiotherapy for
prostate cancer: a single-institution matched-pair analysis’, International Journal of
Radiation Oncology, Biology, Physics, 76 (1), 43-49.
Pinkawa, M., Asadpour, B. et al (2009). ‘Health-related quality of life after permanent I125 brachytherapy and conformal external beam radiotherapy for prostate cancer: a
matched-pair comparison’, Radiotherapy and Oncology, 91 (2), 225–231.
Pinnock, C.B., Stapleton, A.M. & Marshall, V.R. (1999). ‘Erectile dysfunction in the
community: a prevalence study’, Medical Journal of Australia, 171 (7), 353–357.
Pinsky, P.F., Andriole, G. et al (2007). ‘Prostate-specific antigen velocity and prostate
cancer Gleason grade and stage’, Cancer, 109 (8), 1689–1695.
Potters, L., Purrazzella, R. et al (2003). ‘The prognostic significance of Gleason Grade in
patients treated with permanent prostate brachytherapy’, International Journal of
Radiation Oncology, Biology, Physics, 56 (3), 749–754.
Pound, C.R., Partin, A.W. et al (1999). ‘Natural history of progression after PSA elevation
following radical prostatectomy’, JAMA, 281 (17), 1591–1597.
Productivity Commission (2010). ‘Public and private hospitals: multivariate analysis’,
Supplement to Research Report, Canberra.
Rasiah, K.K., Stricker, P.D. et al (2003). ‘Prognostic significance of Gleason pattern in
patients with Gleason score 7 prostate carcinoma’, Cancer, 98 (12), 2560–2565.
Rassweiler, J., Seemann, O. et al (2003). ‘Laparoscopic versus open radical prostatectomy:
a comparative study at a single institution’, Journal of Urology, 169 (5), 1689–1693.
Reed, D.R., Wallner, K.E. et al (2007). ‘A prospective randomized comparison of
stranded vs. loose 125I seeds for prostate brachytherapy’, Brachytherapy, 6 (2), 129–134.
Roach, M. 3rd, Hanks, G. et al (2006). ‘Defining biochemical failure following
radiotherapy with or without hormonal therapy in men with clinically localized prostate
cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference’,
International Journal of Radiation Oncology, Biology, Physics, 65 (4), 965-974.
Roemeling, S., Roobol, M.J. et al (2007). ‘Active surveillance for prostate cancers detected
in three subsequent rounds of a screening trial: characteristics, PSA doubling times, and
outcome’, European Urology, 51 (5), 1244-1250, discussion 1251.
Sacco, D.E., Daller, M. et al (2003). ‘Corticosteroid use after prostate brachytherapy
reduces the risk of acute urinary retention’, BJU International, 91 (4), 345-349.
Schafer, J.W., Welzel, G. et al (2008). ‘Long-term health-related quality-of-life outcomes
after permanent prostate brachytherapy’, Onkologie, 31 (11), 599-603.
Page 258 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Shao, Y.H., Demissie, K. et al (2009). ‘Contemporary risk profile of prostate cancer in the
United States’, Journal of the National Cancer Institute, 101 (18), 1280–1283.
Skwarchuk, M.W., Jackson, A. et al (2000). ‘Late rectal toxicity after conformal
radiotherapy of prostate cancer (I): multivariate analysis and dose-response’, International
Journal of Radiation Oncology, Biology, Physics, 47 (1), 103–113.
Smith, D.P., King, M.T. et al (2010). ‘Quality of life three years after diagnosis of localised
prostate cancer: population-based cohort study’, BMJ, 340 (7739), 195.
Sobin, L.H., Gospodarowicz, M.K. & Whittekind, C.H. (eds) (2009). TNM classification
of malignant tumours (7th edn), Wiley-Blackwell, Oxford.
Soloway, M.S., Soloway, C.T. et al (2010). ‘Careful selection and close monitoring of lowrisk prostate cancer patients on active surveillance minimizes the need for treatment’,
European Urology 58 (6), 831–835.
Stamey, T.A., Caldwell, M. et al (2004). ‘The prostate specific antigen era in the United
States is over for prostate cancer: what happened in the last 20 years?’, Journal of
Urology, 172 (4 pt 1), 1297–1301.
Stamey, T.A., Yang, N. et al (1987). ‘Prostate-specific antigen as a serum marker for
adenocarcinoma of the prostate’, New England Journal of Medicine, 317 (15), 909–916.
Stark, J.R., Perner, S. et al (2009). ‘Gleason score and lethal prostate cancer: does 3 + 4 =
4 + 3?’, Journal of Clinical Oncology, 27 (21), 3459–3464.
Stenman, U.H., Hakama, M. et al (1994). ‘Serum concentrations of prostate specific
antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate
cancer’, Lancet, 344 (8937), 1594–1598.
Stephenson, A.J., Scardino, P.T. et al (2005). ‘Postoperative nomogram predicting the 10year probability of prostate cancer recurrence after radical prostatectomy’, Journal of
Clinical Oncology, 23 (28), 7005–7012.
Stewart, S.T., Lenert, L. et al (2005). ‘Utilities for prostate cancer health states in men
aged 60 and older’, Medical Care, 43 (4), 347–355.
Stock, R.G. & Stone, N.N. (2002). ‘Importance of post-implant dosimetry in permanent
prostate brachytherapy’, European Urology, 41 (4), 434–439.
Stokes, S.H. (2000). ‘Comparison of biochemical disease-free survival of patients with
localized carcinoma of the prostate undergoing radical prostatectomy, transperineal
ultrasound-guided radioactive seed implantation, or definitive external beam irradiation’,
International Journal of Radiation Oncology, Biology, Physics, 47 (1), 129–136.
Stone, N.N., Marshall, D.T. et al (2010). ‘Does neoadjuvant hormonal therapy improve
urinary function when given to men with large prostates undergoing prostate
brachytherapy?’, Journal of Urology, 183 (2), 634–639.
Sullivan, P.W. & Ghushchyan, V. (2006). ‘Preference-based EQ-5D index scores for
chronic conditions in the United States’, Medical Decision Making, 26 (4), 410–420.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 259 of 261
Tanaka, N., Asakawa, I. et al (2009). ‘Technical acquisition and dosimetric assessment of
iodine-125 permanent brachytherapy in localized prostate cancer: our first series of 100
patients’, International Journal of Urology, 16 (1), 70–74.
Thompson, A., Keyes, M. et al (2010). ‘Evaluating the Phoenix definition of biochemical
failure after (125)I prostate brachytherapy: can PSA kinetics distinguish PSA failures from
PSA bounces?’, International Journal of Radiation Oncology, Biology, Physics, 78 (2),
415–421.
Thompson, D.E., Mabuchi, K. et al (1994). ‘Cancer incidence in atomic bomb survivors.
Part II: solid tumors, 1958–1987’, Radiation Research, 137 (2 suppl.), S17–S67.
Tsui, G., Gillan, C. et al (2005). ‘Post-treatment complications of early-stage prostate
cancer patients: Brachytherapy versus three-dimensional conformal radiation therapy’,
Cancer Journal, 11 (2), 122–132.
van den Bergh, R.C., Roemeling, S. et al (2009). ‘Outcomes of men with screen-detected
prostate cancer eligible for active surveillance who were managed expectantly’, European
Urology, 55 (1), 1–8.
van den Bergh, R.C., Vasarainen, H. et al (2010). ‘Short-term outcomes of the prospective
multicentre ‘Prostate Cancer Research International: Active Surveillance’ study’, BJU
International, 105 (7), 956–962.
Vicini, F.A., Martinez, A. et al (2002). ‘An interinstitutional and interspecialty comparison
of treatment outcome data for patients with prostate carcinoma based on predefined
prognostic categories and minimum follow-up’, Cancer, 95 (10), 2126–2135.
Wallner, K., Merrick, G. et al (2003). ‘125I versus 103Pd for low-risk prostate cancer:
preliminary PSA outcomes from a prospective randomized multicenter trial’,
International Journal of Radiation Oncology, Biology, Physics, 57 (5), 1297–1303.
Walsh, P.C. & Donker, P.J. (1982). ‘Impotence following radical prostatectomy: insight
into etiology and prevention’, Journal of Urology, 128 (3), 492–497.
Walsh, P.C., Lepor, H. & Eggleston, J.C. (1983). ‘Radical prostatectomy with preservation
of sexual function: anatomical and pathological considerations’, Prostate, 4 (5), 473–485.
Wei, J.T., Dunn, R.L. et al (2000). ‘Development and validation of the expanded prostate
cancer index composite (EPIC) for comprehensive assessment of health-related quality of
life in men with prostate cancer’, Urology, 56 (6), 899–905.
Wei, J.T., Dunn, R.L. et al (2002). ‘Comprehensive comparison of health-related quality
of life after contemporary therapies for localized prostate cancer’, Journal of Clinical
Oncology, 20 (2), 557–566.
Welte, R., Feenstra, T. et al (2004). ‘A decision chart for assessing and improving the
transferability of economic evaluation results between countries’, Pharmacoeconomics,
22 (13), 857–876.
Whitmore, W.F. Jr., Hilaris, B. & Grabstald, H. (1972). ‘Retropubic implantation to
iodine 125 in the treatment of prostatic cancer’, Journal of Urology, 108 (6), 918–920.
Page 260 of 261
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Wilt, T. J. (2008). ‘SPCG-4: a needed START to PIVOTal data to promote and protect
evidence-based prostate cancer care’, Journal of the National Cancer Institute, 100 (16),
1123–1125.
Wong, W.W., Vora, S.A. et al (2009). ‘Radiation dose escalation for localized prostate
cancer intensity-modulated radiotherapy versus permanent transperineal brachytherapy’,
Cancer, 115 (23), 5596–5606.
Wyler, S.F., Engeler, D.S. et al (2009). ‘Health-related quality of life after radical
prostatectomy and low-dose-rate brachytherapy for localized prostate cancer’, Urologia
Internationalis, 82 (1), 17–23.
Zeegers, M.P., Goldbohm, R.A. & van den Brandt, P.A. (2002). ‘A prospective study on
active and environmental tobacco smoking and bladder cancer risk (The Netherlands)’,
Cancer Causes Control, 13 (1), 83–90.
Zelefsky, M.J., Chan, H. et al (2006). ‘Long-term outcome of high dose intensity
modulated radiation therapy for patients with clinically localized prostate cancer’, Journal
of Urology, 176 (4 pt 1), 1415–1419.
Zelefsky, M.J. & Whitmore, W.F. Jr. (1997). ‘Long-term results of retropubic permanent
125iodine implantation of the prostate for clinically localized prostatic cancer’, Journal of
Urology, 158 (1), 23–29; discussion 29–30.
Zelefsky, M.J., Yamada, Y. et al (2007a). ‘Intraoperative real-time planned conformal
prostate brachytherapy: post-implantation dosimetric outcome and clinical implications’,
Radiotherapy and Oncology, 84 (2), 185–189.
Zelefsky, M.J., Yamada, Y. et al (2007b). ‘Five-year outcome of intraoperative conformal
permanent I-125 interstitial implantation for patients with clinically localized prostate
cancer’, International Journal of Radiation Oncology, Biology, Physics, 67 (1), 65–70.
Zeliadt, S.B., Potosky, A.L. et al (2006). ‘Survival benefit associated with adjuvant
androgen deprivation therapy combined with radiotherapy for high- and low-risk patients
with nonmetastatic prostate cancer’, International Journal of Radiation Oncology,
Biology, Physics, 66 (2), 395–402.
Zhou, E.H., Ellis, R.T. et al (2009). ‘Radiotherapy and survival in prostate cancer patients:
a population-based study’, International Journal of Radiation Oncology, Biology, Physics,
73 (1), 15–23.
Brachytherapy for the treatment of prostate cancer – MSAC 1089.1
Page 261 of 261